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CHAPTER 2 LITERATURE REVIEW 2

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CHAPTER 2
LITERATURE REVIEW
2.1Neuroprotection
Neuroprotection is defined as the comparative mechanism and its strategies that are able to protect the central nervous system (CNS) from the neuronal injuries that is due to the neurodegenerative disorders ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”pRndXcW3″,”properties”:{“formattedCitation”:”(Kumar and Khanum, 2012)”,”plainCitation”:”(Kumar and Khanum, 2012)”,”noteIndex”:0},”citationItems”:{“id”:21,”uris”:”http://zotero.org/users/local/izdntZkG/items/B5UX649U”,”uri”:”http://zotero.org/users/local/izdntZkG/items/B5UX649U”,”itemData”:{“id”:21,”type”:”article-journal”,”title”:”Neuroprotective potential of phytochemicals”,”container-title”:”Pharmacognosy Reviews”,”page”:”81-90″,”volume”:”6″,”issue”:”12″,”source”:”PubMed”,”abstract”:”Cognitive dysfunction is a major health problem in the 21st century, and many neuropsychiatric disorders and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer’s Disease dementia, cerebrovascular impairment, seizure disorders, head injury and Parkinsonism, can be severly functionally debilitating in nature. In course of time, a number of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well newer molecules have been tried against these targets. Phytochemicals from medicinal plants play a vital role in maintaining the brain’s chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional practice of medicine, several plants have been reported to treat cognitive disorders. In this review paper, we attempt to throw some light on the use of medicinal herbs to treat cognitive disorders. In this review, we briefly deal with some medicinal herbs focusing on their neuroprotective active phytochemical substances like fatty acids, phenols, alkaloids, flavonoids, saponins, terpenes etc. The resistance of neurons to various stressors by activating specific signal transduction pathways and transcription factors are also discussed. It was observed in the review that a number of herbal medicines used in Ayurvedic practices as well Chinese medicines contain multiple compounds and phytochemicals that may have a neuroprotective effect which may prove beneficial in different neuropsychiatric and neurodegenerative disorders. Though the presence of receptors or transporters for polyphenols or other phytochemicals of the herbal preparations, in brain tissues remains to be ascertained, compounds with multiple targets appear as a potential and promising class of therapeutics for the treatment of diseases with a multifactorial etiology.”,”DOI”:”10.4103/0973-7847.99898″,”ISSN”:”0976-2787″,”note”:”PMID: 23055633
PMCID: PMC3459459″,”journalAbbreviation”:”Pharmacogn Rev”,”language”:”eng”,”author”:{“family”:”Kumar”,”given”:”G. Phani”},{“family”:”Khanum”,”given”:”Farhath”},”issued”:{“date-parts”:”2012″,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kumar and Khanum, 2012). According to ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”s7KHP2vK”,”properties”:{“formattedCitation”:”(Vajda, 2002)”,”plainCitation”:”(Vajda, 2002)”,”noteIndex”:0},”citationItems”:{“id”:23,”uris”:”http://zotero.org/users/local/izdntZkG/items/VSF3VBNB”,”uri”:”http://zotero.org/users/local/izdntZkG/items/VSF3VBNB”,”itemData”:{“id”:23,”type”:”article-journal”,”title”:”Neuroprotection and neurodegenerative disease”,”container-title”:”Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia”,”page”:”4-8″,”volume”:”9″,”issue”:”1″,”source”:”PubMed”,”abstract”:”This paper will focus on commonalities in the aetiology and pathology in five areas of neurological disease with illustrative examples of therapy. Possibilities of multimodal and neuroprotective therapies in human disease, employing currently available drugs and showing evidence of neuroprotective potential in animal models, are discussed. By definition, neuroprotection is an effect that may result in salvage, recovery or regeneration of the nervous system, its cells, structure and function. It is thought that there are many neurochemical modulators of nervous system damage. In epilepsy, excessive glutamate-mediated neurotransmission, impaired voltage sensitive sodium and calcium channel functioning, impaired GABA-mediated inhibition and alterations in acid base balance, when set in motion, may trigger a cascade of events leading to neuronal damage and cell death. Acute and chronic nervous system damage in response to an insult may lead to acute or delayed neuronal death, apoptotic cell death, neuronal degeneration, injury and loss, and gliosis. Cell death in the CNS following injury can occur in the manner of apoptosis, necrosis or hybrid forms. In general, NMDA receptor and non-NMDA receptor mediated excitotoxic injury results in neurodegeneration along an apoptosis-necrosis continuum. The effects of neuronal injury depend on factors including the degree of brain maturity or site of the lesion. There is some evidence supporting the hypothesis that neuroprotection may be a practical and achievable target using drugs already available, at present employed only for limited indications. Using these drugs early in the disease, may save decades of development of new drugs, which would require evaluation in animal studies, and human clinical trials. New drugs would also need to be shown to be safe and acceptable, physiologically not detrimental to humans and free from idiosyncratic adverse effects.”,”DOI”:”10.1054/jocn.2001.1027″,”ISSN”:”0967-5868″,”note”:”PMID: 11749009″,”journalAbbreviation”:”J Clin Neurosci”,”language”:”eng”,”author”:{“family”:”Vajda”,”given”:”Frank J. E.”},”issued”:{“date-parts”:”2002″,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} Vajda (2002), neuroprotection refers to the consequence that might arise in salvage, recover of CNS, its cells and even the function of the CNS. Besides, Lalkovi?ová and Danielisová (2016) stressed that neuroprotection is broadly studied treatment option for many CNS diseases. The strategies of neuroprotection including to retain neuronal integrity or to keep the already damaged cell to functioning ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”47K2ZEfZ”,”properties”:{“formattedCitation”:”(Falsini et al., 2013)”,”plainCitation”:”(Falsini et al., 2013)”,”noteIndex”:0},”citationItems”:{“id”:74,”uris”:”http://zotero.org/users/local/izdntZkG/items/24PGYXVA”,”uri”:”http://zotero.org/users/local/izdntZkG/items/24PGYXVA”,”itemData”:{“id”:74,”type”:”chapter”,”title”:”Chapter 37 – Neuroprotection”,”container-title”:”Retina (Fifth Edition)”,”publisher”:”W.B. Saunders”,”publisher-place”:”London”,”page”:”716-733″,”source”:”ScienceDirect”,”event-place”:”London”,”URL”:”https://www.sciencedirect.com/science/article/pii/B9781455707379000370″,”ISBN”:”978-1-4557-0737-9″,”note”:”DOI: 10.1016/B978-1-4557-0737-9.00037-0″,”author”:{“family”:”Falsini”,”given”:”Benedetto”},{“family”:”Bush”,”given”:”Ronald A.”},{“family”:”Sieving”,”given”:”Paul A.”},”editor”:{“family”:”Ryan”,”given”:”Stephen J.”},{“family”:”Sadda”,”given”:”SriniVas R.”},{“family”:”Hinton”,”given”:”David R.”},{“family”:”Schachat”,”given”:”Andrew P.”},{“family”:”Sadda”,”given”:”SriniVas R.”},{“family”:”Wilkinson”,”given”:”C. P.”},{“family”:”Wiedemann”,”given”:”Peter”},{“family”:”Schachat”,”given”:”Andrew P.”},”issued”:{“date-parts”:”2013″},”accessed”:{“date-parts”:”2018″,4,6}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Falsini et al., 2013). Other than that, neuroprotective strategies are strongly required to protect the brain from drugs and toxic effects of various chemicals. For instance, many neuronal can be damage by substantial process and biochemical reactions. Hence, these processes can be result to apoptosis which is programmed cell death or necrotic cell death. This can causes irreversible damage ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”QLY8udyI”,”properties”:{“formattedCitation”:”(Lalkovi\uc0\u269{}ov\uc0\u225{} and Danielisov\uc0\u225{}, 2016)”,”plainCitation”:”(Lalkovi?ová and Danielisová, 2016)”,”noteIndex”:0},”citationItems”:{“id”:68,”uris”:”http://zotero.org/users/local/izdntZkG/items/Y4JEQKRV”,”uri”:”http://zotero.org/users/local/izdntZkG/items/Y4JEQKRV”,”itemData”:{“id”:68,”type”:”article-journal”,”title”:”Neuroprotection and antioxidants”,”container-title”:”Neural Regeneration Research”,”page”:”865-874″,”volume”:”11″,”issue”:”6″,”source”:”PubMed Central”,”abstract”:”Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality.”,”DOI”:”10.4103/1673-5374.184447″,”ISSN”:”1673-5374″,”note”:”PMID: 27482198
PMCID: PMC4962567″,”journalAbbreviation”:”Neural Regen Res”,”author”:{“family”:”Lalkovi?ová”,”given”:”Maria”},{“family”:”Danielisová”,”given”:”Viera”},”issued”:{“date-parts”:”2016″,6}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Lalkovi?ová and Danielisová, 2016). Currently, the medications for neurodegenerative disorders are only to decrease the symptoms that appeared in someone ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”dccAZZJ4″,”properties”:{“formattedCitation”:”(Yacoubian, 2017)”,”plainCitation”:”(Yacoubian, 2017)”,”noteIndex”:0},”citationItems”:{“id”:97,”uris”:”http://zotero.org/users/local/izdntZkG/items/WKANLYHQ”,”uri”:”http://zotero.org/users/local/izdntZkG/items/WKANLYHQ”,”itemData”:{“id”:97,”type”:”chapter”,”title”:”Chapter 1 – Neurodegenerative Disorders: Why Do We Need New Therapies?”,”container-title”:”Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders”,”publisher”:”Academic Press”,”page”:”1-16″,”source”:”ScienceDirect”,”abstract”:”Neurodegenerative disorders are marked by the loss of neurons within the brain and/or spinal cord. The clinical features of this diverse group of neurological disorders depend on the particular central nervous system regions involved. The two most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease. With the aging of the general population, the prevalence of these disorders is expected to rise dramatically in the next few decades, with a resultant increase in the societal and financial burden of these disorders. Currently, medications for this group of disorders are limited and aim to treat the symptoms only. None of the currently available therapies slow or stop the continued loss of neurons. A better understanding of the mechanisms underlying neurodegeneration should lead to more effective, disease-modifying treatments in the future.”,”URL”:”https://www.sciencedirect.com/science/article/pii/B9780128028100000015″,”ISBN”:”978-0-12-802810-0″,”note”:”DOI: 10.1016/B978-0-12-802810-0.00001-5″,”shortTitle”:”Chapter 1 – Neurodegenerative Disorders”,”author”:{“family”:”Yacoubian”,”given”:”T. A.”},”editor”:{“family”:”Adejare”,”given”:”Adeboye”},”issued”:{“date-parts”:”2017″},”accessed”:{“date-parts”:”2018″,4,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Yacoubian, 2017). Therefore, neuroprotection and prevention of neurodegeneration diseases are very crucial and highly important topic to investigate and deeply studied ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”55TfTe8y”,”properties”:{“formattedCitation”:”(Lalkovi\uc0\u269{}ov\uc0\u225{} and Danielisov\uc0\u225{}, 2016)”,”plainCitation”:”(Lalkovi?ová and Danielisová, 2016)”,”noteIndex”:0},”citationItems”:{“id”:68,”uris”:”http://zotero.org/users/local/izdntZkG/items/Y4JEQKRV”,”uri”:”http://zotero.org/users/local/izdntZkG/items/Y4JEQKRV”,”itemData”:{“id”:68,”type”:”article-journal”,”title”:”Neuroprotection and antioxidants”,”container-title”:”Neural Regeneration Research”,”page”:”865-874″,”volume”:”11″,”issue”:”6″,”source”:”PubMed Central”,”abstract”:”Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality.”,”DOI”:”10.4103/1673-5374.184447″,”ISSN”:”1673-5374″,”note”:”PMID: 27482198
PMCID: PMC4962567″,”journalAbbreviation”:”Neural Regen Res”,”author”:{“family”:”Lalkovi?ová”,”given”:”Maria”},{“family”:”Danielisová”,”given”:”Viera”},”issued”:{“date-parts”:”2016″,6}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Lalkovi?ová and Danielisová, 2016).

2.2Neurodegenerative disease
Neurodegenerative disease is specified by slow progressive as the loss of neurons in the CNS. This causes deficiency in particular brain functions such as movement, memory and cognition performed by the affected CNS region ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”vTHdY464″,”properties”:{“formattedCitation”:”(Gao and Hong, 2008)”,”plainCitation”:”(Gao and Hong, 2008)”,”noteIndex”:0},”citationItems”:{“id”:92,”uris”:”http://zotero.org/users/local/izdntZkG/items/KYAYDL7S”,”uri”:”http://zotero.org/users/local/izdntZkG/items/KYAYDL7S”,”itemData”:{“id”:92,”type”:”article-journal”,”title”:”Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression”,”container-title”:”Trends in immunology”,”page”:”357-365″,”volume”:”29″,”issue”:”8″,”source”:”PubMed Central”,”abstract”:”Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases.”,”DOI”:”10.1016/j.it.2008.05.002″,”ISSN”:”1471-4906″,”note”:”PMID: 18599350
PMCID: PMC4794280″,”shortTitle”:”Why neurodegenerative diseases are progressive”,”journalAbbreviation”:”Trends Immunol”,”author”:{“family”:”Gao”,”given”:”Hui-Ming”},{“family”:”Hong”,”given”:”Jau-Shyong”},”issued”:{“date-parts”:”2008″,8}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Gao and Hong, 2008). The clinical features of neurological disorders are depending on the specific CNS involved. Alzheimer’s disease and Parkinson’s disease are the two most common result of neurodegenerative disorders ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”63ApQeNC”,”properties”:{“formattedCitation”:”(Yacoubian, 2017)”,”plainCitation”:”(Yacoubian, 2017)”,”noteIndex”:0},”citationItems”:{“id”:97,”uris”:”http://zotero.org/users/local/izdntZkG/items/WKANLYHQ”,”uri”:”http://zotero.org/users/local/izdntZkG/items/WKANLYHQ”,”itemData”:{“id”:97,”type”:”chapter”,”title”:”Chapter 1 – Neurodegenerative Disorders: Why Do We Need New Therapies?”,”container-title”:”Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders”,”publisher”:”Academic Press”,”page”:”1-16″,”source”:”ScienceDirect”,”abstract”:”Neurodegenerative disorders are marked by the loss of neurons within the brain and/or spinal cord. The clinical features of this diverse group of neurological disorders depend on the particular central nervous system regions involved. The two most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease. With the aging of the general population, the prevalence of these disorders is expected to rise dramatically in the next few decades, with a resultant increase in the societal and financial burden of these disorders. Currently, medications for this group of disorders are limited and aim to treat the symptoms only. None of the currently available therapies slow or stop the continued loss of neurons. A better understanding of the mechanisms underlying neurodegeneration should lead to more effective, disease-modifying treatments in the future.”,”URL”:”https://www.sciencedirect.com/science/article/pii/B9780128028100000015″,”ISBN”:”978-0-12-802810-0″,”note”:”DOI: 10.1016/B978-0-12-802810-0.00001-5″,”shortTitle”:”Chapter 1 – Neurodegenerative Disorders”,”author”:{“family”:”Yacoubian”,”given”:”T. A.”},”editor”:{“family”:”Adejare”,”given”:”Adeboye”},”issued”:{“date-parts”:”2017″},”accessed”:{“date-parts”:”2018″,4,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Yacoubian, 2017). However, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury, multiple sclerosis and glaucoma are also type of neurodegenerative diseases that are commonly occurred to human. Despite their dissimilar triggering events, a fundamental feature is chronic immune activation that is located in a particular of microglia, the resident macrophages of CNS ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”BNpUSjyI”,”properties”:{“formattedCitation”:”(Amor et al., 2010)”,”plainCitation”:”(Amor et al., 2010)”,”noteIndex”:0},”citationItems”:{“id”:99,”uris”:”http://zotero.org/users/local/izdntZkG/items/RLI6HKR7″,”uri”:”http://zotero.org/users/local/izdntZkG/items/RLI6HKR7″,”itemData”:{“id”:99,”type”:”article-journal”,”title”:”Inflammation in neurodegenerative diseases”,”container-title”:”Immunology”,”page”:”154-169″,”volume”:”129″,”issue”:”2″,”source”:”PubMed Central”,”abstract”:”Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Apart from the pathogenic role of immune responses, emerging evidence indicates that immune responses are also critical for neuroregeneration. Here, we review the impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and discuss their contribution to either damage or repair. We also discuss potential therapies aimed at the immune responses within the central nervous system. A better understanding of the interaction between the immune and nervous systems will be crucial to either target pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic neurodegenerative diseases.”,”DOI”:”10.1111/j.1365-2567.2009.03225.x”,”ISSN”:”0019-2805″,”note”:”PMID: 20561356
PMCID: PMC2814458″,”journalAbbreviation”:”Immunology”,”author”:{“family”:”Amor”,”given”:”Sandra”},{“family”:”Puentes”,”given”:”Fabiola”},{“family”:”Baker”,”given”:”David”},{“family”:”Valk”,”given”:”Paul”,”non-dropping-particle”:”van der”},”issued”:{“date-parts”:”2010″,2}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Amor et al., 2010). These diseases are associated with the protein aggregation such as mis-folded of protein, neuroinflammation and oxidative stress.
2.2.1Oxidative stress
Oxidative stress is the outcome of unregulated production of reactive oxygen species (ROS). Oxidative stress is the result of imbalance in pro-oxidant or antioxidant homeostasis. This can trigger the generation of toxic ROS. The types of ROS are hydrogen peroxide, superoxide, nitric oxide and extremely reactive hydroxyl radicals. The reasons of brain tissue being receptive to oxidative damage are including high oxygen consumption, relatively low antioxidant level and low regenerative capacity ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”YG4x5Jvk”,”properties”:{“formattedCitation”:”(Barnham et al., 2004)”,”plainCitation”:”(Barnham et al., 2004)”,”noteIndex”:0},”citationItems”:{“id”:84,”uris”:”http://zotero.org/users/local/izdntZkG/items/6KUE2HLM”,”uri”:”http://zotero.org/users/local/izdntZkG/items/6KUE2HLM”,”itemData”:{“id”:84,”type”:”article-journal”,”title”:”Neurodegenerative diseases and oxidative stress”,”container-title”:”Nature Reviews. Drug Discovery”,”page”:”205-214″,”volume”:”3″,”issue”:”3″,”source”:”PubMed”,”abstract”:”Oxidative stress has been implicated in the progression of Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.”,”DOI”:”10.1038/nrd1330″,”ISSN”:”1474-1776″,”note”:”PMID: 15031734″,”journalAbbreviation”:”Nat Rev Drug Discov”,”language”:”eng”,”author”:{“family”:”Barnham”,”given”:”Kevin J.”},{“family”:”Masters”,”given”:”Colin L.”},{“family”:”Bush”,”given”:”Ashley I.”},”issued”:{“date-parts”:”2004″,3}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Barnham et al., 2004). Moreover, depletion or insufficient synthesis of neurotransmitter, abnormal ubiquitination and damaging of blood brain barrier in the CNS are also linked to the neurodegenerative diseases ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”aHV5DIAt”,”properties”:{“formattedCitation”:”(Rasool et al., 2014)”,”plainCitation”:”(Rasool et al., 2014)”,”noteIndex”:0},”citationItems”:{“id”:102,”uris”:”http://zotero.org/users/local/izdntZkG/items/9KP8LQPF”,”uri”:”http://zotero.org/users/local/izdntZkG/items/9KP8LQPF”,”itemData”:{“id”:102,”type”:”webpage”,”title”:”Recent Updates in the Treatment of Neurodegenerative Disorders Using Natural Compounds”,”container-title”:”Evidence-Based Complementary and Alternative Medicine”,”genre”:”Research article”,”abstract”:”Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS). Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB) in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer’s disease, Parkinson’s disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.”,”URL”:”https://www.hindawi.com/journals/ecam/2014/979730/”,”note”:”PMID: 24864161
DOI: 10.1155/2014/979730″,”language”:”en”,”author”:{“family”:”Rasool”,”given”:”Mahmood”},{“family”:”Malik”,”given”:”Arif”},{“family”:”Qureshi”,”given”:”Muhammad Saeed”},{“family”:”Manan”,”given”:”Abdul”},{“family”:”Pushparaj”,”given”:”Peter Natesan”},{“family”:”Asif”,”given”:”Muhammad”},{“family”:”Qazi”,”given”:”Mahmood Husain”},{“family”:”Qazi”,”given”:”Aamer Mahmood”},{“family”:”Kamal”,”given”:”Mohammad Amjad”},{“family”:”Gan”,”given”:”Siew Hua”},{“family”:”Sheikh”,”given”:”Ishfaq Ahmed”},”issued”:{“date-parts”:”2014″},”accessed”:{“date-parts”:”2018″,4,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Rasool et al., 2014). Disruption of the blood-brain barrier causes acute and chronic cerebral ischemia, brain tumors and brain trauma, Alzheimer’s disease and Parkinson Disease ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”E9cAQ1HO”,”properties”:{“formattedCitation”:”(Rosenberg, 2012)”,”plainCitation”:”(Rosenberg, 2012)”,”noteIndex”:0},”citationItems”:{“id”:267,”uris”:”http://zotero.org/users/local/izdntZkG/items/GFPHKNXG”,”uri”:”http://zotero.org/users/local/izdntZkG/items/GFPHKNXG”,”itemData”:{“id”:267,”type”:”article-journal”,”title”:”Neurological diseases in relation to the blood-brain barrier”,”container-title”:”Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism”,”page”:”1139-1151″,”volume”:”32″,”issue”:”7″,”source”:”PubMed”,”abstract”:”Disruption of the blood-brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity.”,”DOI”:”10.1038/jcbfm.2011.197″,”ISSN”:”1559-7016″,”note”:”PMID: 22252235
PMCID: PMC3390801″,”journalAbbreviation”:”J. Cereb. Blood Flow Metab.”,”language”:”eng”,”author”:{“family”:”Rosenberg”,”given”:”Gary A.”},”issued”:{“date-parts”:”2012″,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Rosenberg, 2012).

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2.2.2Parkinson’s disease
Parkinson’s disease (PD) is a type of neurodegenerative disease which can cause impaired motor system function in body. The characteristics of early PD are difficult to walk, slowly movement and the most obvious is shaking excessively which can interfere daily activities ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”V3215U6y”,”properties”:{“formattedCitation”:”(Sveinbjornsdottir, 2016)”,”plainCitation”:”(Sveinbjornsdottir, 2016)”,”noteIndex”:0},”citationItems”:{“id”:207,”uris”:”http://zotero.org/users/local/izdntZkG/items/XC95Y9ZS”,”uri”:”http://zotero.org/users/local/izdntZkG/items/XC95Y9ZS”,”itemData”:{“id”:207,”type”:”article-journal”,”title”:”The clinical symptoms of Parkinson’s disease”,”container-title”:”Journal of Neurochemistry”,”page”:”318-324″,”volume”:”139 Suppl 1″,”source”:”PubMed”,”abstract”:”In this review, the clinical features of Parkinson’s disease, both motor and non-motor, are described in the context of the progression of the disease. Also briefly discussed are the major treatment strategies and their complications. Parkinson’s disease is a slowly progressing neurodegenerative disorder, causing impaired motor function with slow movements, tremor and gait and balance disturbances. A variety of non-motor symptoms are common in Parkinson’s disease. They include disturbed autonomic function with orthostatic hypotension, constipation and urinary disturbances, a variety of sleep disorders and a spectrum of neuropsychiatric symptoms. This article describes the different clinical symptoms that may occur and the clinical course of the disease. This article is part of a special issue on Parkinson disease.”,”DOI”:”10.1111/jnc.13691″,”ISSN”:”1471-4159″,”note”:”PMID: 27401947″,”journalAbbreviation”:”J. Neurochem.”,”language”:”eng”,”author”:{“family”:”Sveinbjornsdottir”,”given”:”Sigurlaug”},”issued”:{“date-parts”:”2016″,10}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Sveinbjornsdottir, 2016). PD is a common movement disorder and 1% of adults older than 60 years can be affected ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”rCh6bUrS”,”properties”:{“formattedCitation”:”(Samii et al., 2004)”,”plainCitation”:”(Samii et al., 2004)”,”noteIndex”:0},”citationItems”:{“id”:215,”uris”:”http://zotero.org/users/local/izdntZkG/items/UEZT2B48″,”uri”:”http://zotero.org/users/local/izdntZkG/items/UEZT2B48″,”itemData”:{“id”:215,”type”:”article-journal”,”title”:”Parkinson’s disease”,”container-title”:”The Lancet”,”page”:”1783-1793″,”volume”:”363″,”issue”:”9423″,”source”:”www.thelancet.com”,”abstract”:”<h2>Summary</h2><p>Parkinson’s disease is the most common serious movement disorder in the world, affecting about 1% of adults older than 60 years. The disease is attributed to selective loss of neurons in the substantia nigra, and its cause is enigmatic in most individuals. Symptoms of Parkinson’s disease respond in varying degrees to drugs, and surgery offers hope for patients no longer adequately controlled in this manner. The high prevalence of the disease, and important advances in its management, mean that generalists need to have a working knowledge of this disorder. This Seminar covers the basics, from terminology to aspects of diagnosis, treatment, and pathogenesis.</p>”,”DOI”:”10.1016/S0140-6736(04)16305-8″,”ISSN”:”0140-6736, 1474-547X”,”note”:”PMID: 15172778, 15172778″,”journalAbbreviation”:”The Lancet”,”language”:”English”,”author”:{“family”:”Samii”,”given”:”Ali”},{“family”:”Nutt”,”given”:”John G.”},{“family”:”Ransom”,”given”:”Bruce R.”},”issued”:{“date-parts”:”2004″,5,29}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Samii et al., 2004). According to the ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”j2KWCRAZ”,”properties”:{“formattedCitation”:”(Morgan et al., 2017)”,”plainCitation”:”(Morgan et al., 2017)”,”noteIndex”:0},”citationItems”:{“id”:218,”uris”:”http://zotero.org/users/local/izdntZkG/items/5XQ8BLNS”,”uri”:”http://zotero.org/users/local/izdntZkG/items/5XQ8BLNS”,”itemData”:{“id”:218,”type”:”article-journal”,”title”:”Ghrelin mediated neuroprotection – A possible therapy for Parkinson’s disease?”,”container-title”:”Neuropharmacology”,”source”:”ScienceDirect”,”abstract”:”Parkinson’s disease is a common age-related neurodegenerative disorder affecting 10 million people worldwide, but the mechanisms underlying its pathogenesis are still unclear. The disease is characterised by dopamine nerve cell loss in the mid-brain and intra-cellular accumulation of ?-synuclein that results in motor and non-motor dysfunction. In this review, we discuss the neuroprotective effects of the stomach hormone, ghrelin, in models of Parkinson’s disease. Recent findings suggest that it may modulate mitochondrial function and autophagic clearance of impaired organelle in response to changes in cellular energy balance. We consider the putative cellular mechanisms underlying ghrelin-action and the possible role of ghrelin mimetics in slowing or preventing Parkinson’s disease progression.”,”URL”:”http://www.sciencedirect.com/science/article/pii/S002839081730624X”,”DOI”:”10.1016/j.neuropharm.2017.12.027″,”ISSN”:”0028-3908″,”journalAbbreviation”:”Neuropharmacology”,”author”:{“family”:”Morgan”,”given”:”Alwena H.”},{“family”:”Rees”,”given”:”Daniel J.”},{“family”:”Andrews”,”given”:”Zane B.”},{“family”:”Davies”,”given”:”Jeffrey S.”},”issued”:{“date-parts”:”2017″,12,23},”accessed”:{“date-parts”:”2018″,4,8}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} Morgan et al. (2017), PD can occurs to older people because of the dopamine nerve cell loss within the mid-brain and intra-cellular accumulation of ?-synuclein. The aggregation of ?-synuclein can be dispersed to other cell by direct or indirect contact. Therefore, it can causes motor and non-motor system to become dysfunction. It is reported that ghrelin is a possible therapy not only to treat PD patient, but can only treat Alzheimer’s disease.
2.2.3Alzheimer’s disease
Alzheimer’s disease (AD) is a type of neurodegenerative disorder that is irreversible, progressive brain disorder that will slowly knocks down someone’s memory and thinking skills ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”6OvHt6NO”,”properties”:{“formattedCitation”:”(de Almeida et al., 2018)”,”plainCitation”:”(de Almeida et al., 2018)”,”noteIndex”:0},”citationItems”:{“id”:263,”uris”:”http://zotero.org/users/local/izdntZkG/items/PEADJUHE”,”uri”:”http://zotero.org/users/local/izdntZkG/items/PEADJUHE”,”itemData”:{“id”:263,”type”:”article-journal”,”title”:”Discovery of novel dual acetylcholinesterase inhibitors with antifibrillogenic activity related to Alzheimer’s disease”,”container-title”:”Future Medicinal Chemistry”,”source”:”PubMed”,”abstract”:”AIM: Alzheimer’s disease is a progressive and neurodegenerative disorder of the CNS, affecting elderly people. The current pharmacological approach is based on the improvement of cholinergic neurotransmission by inhibiting acetylcholinesterase (AChE) with AChE inhibitors. The disease is also characterized by the accelerated accumulation of ?-amyloid plaques around neurons. Furthermore, in vitro studies revealed that AChE can induce ?-amyloid peptide (A?) aggregation.
METHODOLOGY: Computer-aided molecular design by virtual screening was here employed to discover novel potential AChE inhibitors, with antifibrillogenic properties, in other words, inhibiting A? aggregation.
RESULTS: Compounds 1, 4 and 6 showed interesting AChE inhibition. In addition, they particularly inhibit A? aggregation in vitro, indicating to be promising novel anti-Alzheimer agents.”,”DOI”:”10.4155/fmc-2017-0201″,”ISSN”:”1756-8927″,”note”:”PMID: 29676170″,”journalAbbreviation”:”Future Med Chem”,”language”:”eng”,”author”:{“family”:”Almeida”,”given”:”Jonathan R.”,”non-dropping-particle”:”de”},{“family”:”Figueiro”,”given”:”Micheli”},{“family”:”Almeida”,”given”:”Wanda Pereira”},{“family”:”Paula da Silva”,”given”:”Carlos Henrique Tomich”,”non-dropping-particle”:”de”},”issued”:{“date-parts”:”2018″,4,20}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (de Almeida et al., 2018). According to ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”y6Y101RS”,”properties”:{“formattedCitation”:”(Laurent et al., 2018)”,”plainCitation”:”(Laurent et al., 2018)”,”noteIndex”:0},”citationItems”:{“id”:265,”uris”:”http://zotero.org/users/local/izdntZkG/items/JTC8GHHD”,”uri”:”http://zotero.org/users/local/izdntZkG/items/JTC8GHHD”,”itemData”:{“id”:265,”type”:”article-journal”,”title”:”Tau and neuroinflammation: What impact for Alzheimer’s Disease and Tauopathies?”,”container-title”:”Biomedical Journal”,”page”:”21-33″,”volume”:”41″,”issue”:”1″,”source”:”PubMed”,”abstract”:”Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder and the most common type of dementia (60-80% of cases). In 2016, nearly 44 million people were affected by AD or related dementia. AD is characterized by progressive neuronal damages leading to subtle and latter obvious decline in cognitive functions including symptoms such as memory loss or confusion, which ultimately require full-time medical care. Its neuropathology is defined by the extracellular accumulation of amyloid-? (A?) peptide into amyloid plaques, and intraneuronal neurofibrillary tangles (NFT) consisting of aggregated hyper- and abnormal phosphorylation of tau protein. The latter, identified also as Tau pathology, is observed in a broad spectrum of neurological diseases commonly referred to as “Tauopathies”. Besides these lesions, sustained neuroinflammatory processes occur, involving notably micro- and astro-glial activation, which contribute to disease progression. Recent findings from genome wide association studies further support an instrumental role of neuroinflammation. While the interconnections existing between this innate immune response and the amyloid pathogenesis are widely characterized and described as complex, elaborated and evolving, only few studies focused on Tau pathology. An adaptive immune response takes place conjointly during the disease course, as indicated by the presence of vascular and parenchymal T-cell in AD patients’ brain. The underlying mechanisms of this infiltration and its consequences with regards to Tau pathology remain understudied so far. In the present review, we highlight the interplays existing between Tau pathology and the innate/adaptive immune responses.”,”DOI”:”10.1016/j.bj.2018.01.003″,”ISSN”:”2320-2890″,”note”:”PMID: 29673549″,”shortTitle”:”Tau and neuroinflammation”,”journalAbbreviation”:”Biomed J”,”language”:”eng”,”author”:{“family”:”Laurent”,”given”:”Cyril”},{“family”:”Buée”,”given”:”Luc”},{“family”:”Blum”,”given”:”David”},”issued”:{“date-parts”:”2018″,2}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} Laurent et al., (2018), 60 until 80% cases, AD is the usual type of dementia. Moreover, the effect of AD is it can disturb the ability to perform tasks even the simplest one. Furthermore, it is known to be one of the leading causes of death all around the world. Age is the most important threat factor for the development of AD. For example, the majority of AD patients are usually age 65 years or more ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”VjWPx7yt”,”properties”:{“formattedCitation”:”(Guerreiro and Bras, 2015)”,”plainCitation”:”(Guerreiro and Bras, 2015)”,”noteIndex”:0},”citationItems”:{“id”:117,”uris”:”http://zotero.org/users/local/izdntZkG/items/NR34GUS2″,”uri”:”http://zotero.org/users/local/izdntZkG/items/NR34GUS2″,”itemData”:{“id”:117,”type”:”article-journal”,”title”:”The age factor in Alzheimer’s disease”,”container-title”:”Genome Medicine”,”volume”:”7″,”source”:”PubMed Central”,”abstract”:”Alzheimer’s disease is the most common type of dementia, and it is characterized by a decline in memory or other thinking skills. The greatest risk factor for Alzheimer’s disease is advanced age. A recent genome-wide study identified a locus on chromosome 17 associated with the age at onset, and a specific variant in CCL11 is probably responsible for the association. The association of a protective haplotype with a 10-year delay in the onset of Alzheimer’s disease and the identification of a CCL11 variant with possible functional roles in this association might allow the future development of immunomodulators with the potential to halve disease incidence.”,”URL”:”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617238/”,”DOI”:”10.1186/s13073-015-0232-5″,”ISSN”:”1756-994X”,”note”:”PMID: 26482651
PMCID: PMC4617238″,”journalAbbreviation”:”Genome Med”,”author”:{“family”:”Guerreiro”,”given”:”Rita”},{“family”:”Bras”,”given”:”Jose”},”issued”:{“date-parts”:”2015″,10,20},”accessed”:{“date-parts”:”2018″,4,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Guerreiro and Bras, 2015). AD occurs because of the accumulation of Amyloid-beta (A?) and tau pathology within the cortical brain structure and medial temporal lobe ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”bYc12YZ7″,”properties”:{“formattedCitation”:”(Davis et al., 2013)”,”plainCitation”:”(Davis et al., 2013)”,”noteIndex”:0},”citationItems”:{“id”:114,”uris”:”http://zotero.org/users/local/izdntZkG/items/FHVSDP6J”,”uri”:”http://zotero.org/users/local/izdntZkG/items/FHVSDP6J”,”itemData”:{“id”:114,”type”:”article-journal”,”title”:”Episodic-like memory is sensitive to both Alzheimer’s-like pathological accumulation and normal ageing processes in mice”,”container-title”:”Behavioural Brain Research”,”collection-title”:”SI:Medial Temporal Lobe Memory Networks”,”page”:”73-82″,”volume”:”254″,”source”:”ScienceDirect”,”abstract”:”Episodic memory depends on the hippocampus and is sensitive to both Alzheimer’s disease (AD) pathology and normal ageing. We showed previously that 3xTgAD mice express a specific, episodic-memory deficit at 6 months of age in the What-Where-Which occasion (WWWhich) task (Davis, Easton, Eacott and Gigg, 2013). This task requires the integration of object-location and contextual cues to form an episodic-like memory. Here, we explore the cumulative effect of AD pathology on WWWhich memory by testing very young and middle-aged mice (3 and 12 months old, respectively). For comparison, we included an alternative episodic-like task (What-Where-When; WWWhen) and an object temporal order (Recency) task to explore claims that WWWhen types of memory are open to non-episodic solutions. We found that in contrast to their performance at 6 months, 3-month-old 3xTgAD mice formed WWWhich episodic-like memories; however, their performance at this age was poorer than in matched controls. In contrast, 3xTgAD and control animals aged 12 months were both impaired on the WWWhich task. Finally, 3xTgAD mice with a WWWhich deficit were unimpaired in both Recency and WWWhen tasks. These results support conclusions that: (1) young 3xTgAD mice express episodic-like memory, albeit depressed relative to controls; (2) age-related changes result in a deficit on the hippocampal-dependent WWWhich episodic memory task; and (3) control and 3xTgAD mice can use recency (trace strength) rather than episodic-like memory for tasks that contain a temporal ‘When’ component. These results, in combination with our previous findings, support an age-related decline in WWWhich episodic-like memory in mice. Furthermore, this decline is accelerated in the 3xTgAD model.”,”DOI”:”10.1016/j.bbr.2013.03.009″,”ISSN”:”0166-4328″,”journalAbbreviation”:”Behavioural Brain Research”,”author”:{“family”:”Davis”,”given”:”Katherine E.”},{“family”:”Eacott”,”given”:”Madeline J.”},{“family”:”Easton”,”given”:”Alexander”},{“family”:”Gigg”,”given”:”John”},”issued”:{“date-parts”:”2013″,10,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Davis et al., 2013).

2.2.3.1Amyloid-beta
Amyloid-beta plaque is a microscopic brain protein fragment that affects AD. Moreover, the formation of the A? plaque in AD is by generation of the A? peptide. The A? peptides go through the enzymatic cleavages of larger glycoprotein or APP which is also known as amyloid precursor protein ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”jFSEDJUC”,”properties”:{“formattedCitation”:”(Yee et al., 2015)”,”plainCitation”:”(Yee et al., 2015)”,”noteIndex”:0},”citationItems”:{“id”:274,”uris”:”http://zotero.org/users/local/izdntZkG/items/DT5FK9YX”,”uri”:”http://zotero.org/users/local/izdntZkG/items/DT5FK9YX”,”itemData”:{“id”:274,”type”:”article-journal”,”title”:”Stem Cell Therapy for Neurodegenerative Diseases”,”container-title”:”Hanyang Medical Reviews”,”page”:”229″,”volume”:”35″,”issue”:”4″,”source”:”Crossref”,”DOI”:”10.7599/hmr.2015.35.4.229″,”ISSN”:”1738-429X, 2234-4446″,”language”:”en”,”author”:{“family”:”Yee”,”given”:”Jong Zin”},{“family”:”Oh”,”given”:”Ki-Wook”},{“family”:”Kim”,”given”:”Seung Hyun”},”issued”:{“date-parts”:”2015″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Yee et al., 2015). APP plays a largely role in a range of many biological activities such as signaling, neuronal development and neuronal homeostasis. The A? peptide can be observed in the hippocampus region or neocortex (Viswanathan and Greenberg, 2011). The soluble assembly of A? will stimulate the neuronal dysfunction. However, it is also can stimulate the proinflammatory activation of primary microglia ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”QOHbcfTB”,”properties”:{“formattedCitation”:”(Chen et al., 2017)”,”plainCitation”:”(Chen et al., 2017)”,”noteIndex”:0},”citationItems”:{“id”:275,”uris”:”http://zotero.org/users/local/izdntZkG/items/SWB65R6C”,”uri”:”http://zotero.org/users/local/izdntZkG/items/SWB65R6C”,”itemData”:{“id”:275,”type”:”article-journal”,”title”:”Amyloid beta: structure, biology and structure-based therapeutic development”,”container-title”:”Acta Pharmacologica Sinica”,”page”:”1205-1235″,”volume”:”38″,”issue”:”9″,”source”:”www.nature.com”,”abstract”:”Amyloid beta peptide (A?) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by ?- and ?-secretases. A? accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer’s disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of A? are and by what mechanism A? causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer’s disease. In this paper, we review the structures, biological functions, and neurotoxicity role of A?. We also discuss the potential receptors that interact with A? and mediate A? intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer’s disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer’s disease. These prospects include agents acting on A?, its receptors and tau protein, such as small molecules, vaccines and antibodies against A?; inhibitors or modulators of ?- and ?-secretase; A?-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.”,”DOI”:”10.1038/aps.2017.28″,”ISSN”:”1745-7254″,”shortTitle”:”Amyloid beta”,”language”:”en”,”author”:{“family”:”Chen”,”given”:”Guo-fang”},{“family”:”Xu”,”given”:”Ting-hai”},{“family”:”Yan”,”given”:”Yan”},{“family”:”Zhou”,”given”:”Yu-ren”},{“family”:”Jiang”,”given”:”Yi”},{“family”:”Melcher”,”given”:”Karsten”},{“family”:”Xu”,”given”:”H. Eric”},”issued”:{“date-parts”:”2017″,9}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Chen et al., 2017). Based on amyloid hypothesis, A? aggregation will block cell-to-cell communication and the immune cells will activate. The activation of immune cells will generate the neuroinflammation and causes the brain cells to destroy (Alzheimer’s Association, 2017).

2.3NeuroimflammationNeuroinflammation can be defined as inflammation that occurs in the nervous tissue. In AD, neuroinflammatory responses are very complicated or complex and not completely understood by the researchers. This is because neuroinflammatory involved in numerous molecular players, cellular and biochemical response to the injury and infection. Therefore, these responses will be directed to the triggering factors in which it makes the CNS immunity to protect against potentially harms. Microglia will sense milieu modifications that may be disturb homeostasis under the normal condition. However, microglia can also responded to the inflammatory signals that causing neuroinflammation. This condition can be applied when the body is exposed to neurotoxic stimuli, protein accumulation or brain injury ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”IBJxeZB0″,”properties”:{“formattedCitation”:”(Bazan et al., 2012)”,”plainCitation”:”(Bazan et al., 2012)”,”noteIndex”:0},”citationItems”:{“id”:279,”uris”:”http://zotero.org/users/local/izdntZkG/items/GY8AZDT6″,”uri”:”http://zotero.org/users/local/izdntZkG/items/GY8AZDT6″,”itemData”:{“id”:279,”type”:”chapter”,”title”:”Chapter 34 – Neuroinflammation”,”container-title”:”Basic Neurochemistry (Eighth Edition)”,”publisher”:”Academic Press”,”publisher-place”:”New York”,”page”:”610-620″,”source”:”ScienceDirect”,”event-place”:”New York”,”abstract”:”Neuroinflammation comprises biochemical and cellular responses of the nervous system to injury, infection or neurodegenerative diseases. These responses are directed at mitigating the triggering factors by involving CNS immunity to defend against potential harm. Under normal conditions, microglia, the resident CNS immune cells, actively sense milieu modifications that might perturb homeostasis. However, upon exposure to neurotoxic stimuli, ischemic injury, protein accumulation or age-related homeostatic perturbations, microglia respond by upregulating inflammatory signals that lead to neuroinflammation. The innate immune response of the CNS has the capacity to be both protective and toxic; aberrant microglial activation, mitochondrial dysfunction, and protein aggregation can trigger an acute inflammatory response that, if unresolved, becomes chronic and injurious. By the same token, the formation and release of protective/resolving mediators counteract injury by contributing to tissue repair and resolution of inflammation. These mediators include IL-10, resolvins, lipoxins and neuroprotectins. The coordination of these responses is regulated at least in part by the inflammasome, a cluster of cytoplasmic proteins. Neuroinflammation comprises a key set of cellular and molecular responses, the mechanisms of which contributes to the understanding of CNS homeostasis, infection and neurodegenerative diseases. As a result, therapies are being designed to target the immune response in diseases such as multiple sclerosis, and other neurodegenerative diseases (e.g., Alzheimer’s disease).
Publisher Summary
The central nervous system’s (CNS) innate immune response involves intricate signaling circuitry and cellular networks. The primary cells involved in neuroinflammation are the microglia that actively survey the brain micro­environment and upon activation, serve as the resident macrophages in the CNS. Microglia is derived from the bone marrow, and takes up residence in the brain during development, and comprises approx­imately 12% of the cells of the CNS. Microglia functions as a major immune mediator in the CNS and performs the func­tions necessary for recruitment of the immune system. In the mature CNS, microglia are apparently dormant (resting microglia) but are actively monitoring the environment, con­tributing to the maintenance of neurovascular integrity to prevent access of potentially damaging immune system ele­ments, and mitigating inflammation. The phagocytic role of microglia is displayed during early embryonic brain development in which the microglias ingest cellular debris of excess neurons that have undergone programmed cell death. Microglia are involved in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, HIV dementia, retinal degenera­tive diseases and many other conditions.”,”URL”:”https://www.sciencedirect.com/science/article/pii/B9780123749475000341″,”ISBN”:”978-0-12-374947-5″,”note”:”DOI: 10.1016/B978-0-12-374947-5.00034-1″,”author”:{“family”:”Bazan”,”given”:”Nicolas G.”},{“family”:”Halabi”,”given”:”Anasheh”},{“family”:”Ertel”,”given”:”Monica”},{“family”:”Petasis”,”given”:”Nicos A.”},”editor”:{“family”:”Brady”,”given”:”Scott T.”},{“family”:”Siegel”,”given”:”George J.”},{“family”:”Albers”,”given”:”R. Wayne”},{“family”:”Price”,”given”:”Donald L.”},”issued”:{“date-parts”:”2012″},”accessed”:{“date-parts”:”2018″,4,22}},”locator”:”34″},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Bazan et al., 2012). Besides, it also links the interaction between the periphery and CNS. In order to initiate the inflammatory response, amyloid peptides located within the senile plaques and phosphorylated tau that is abnormal in neurofibrillary tangles should be present ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”gt0gEfJq”,”properties”:{“formattedCitation”:”(Dansokho and Heneka, 2017)”,”plainCitation”:”(Dansokho and Heneka, 2017)”,”noteIndex”:0},”citationItems”:{“id”:128,”uris”:”http://zotero.org/users/local/izdntZkG/items/9FIMDX4M”,”uri”:”http://zotero.org/users/local/izdntZkG/items/9FIMDX4M”,”itemData”:{“id”:128,”type”:”article-journal”,”title”:”Neuroinflammatory responses in Alzheimer’s disease”,”container-title”:”Journal of Neural Transmission”,”page”:”1-9″,”source”:”link.springer.com”,”abstract”:”Neuroinflammatory responses in Alzheimer’s disease (AD) are complex and not fully understood. They involve various cellular and molecular players and associate interaction between the central nervous system (CNS) and the periphery. Amyloid peptides within the senile plaques and abnormally phosphorylated tau in neurofibrillary tangles are able to initiate inflammatory responses, in brain of AD patients and in mouse models of this disease. The outcome of these responses on the pathophysiology of AD depends on several factors and can be either beneficial or detrimental. Thus, understanding the role of neuroinflammation in AD could help to develop safer and more efficient therapeutic strategies. This review discusses recent knowledge on microglia responses toward amyloid and tau pathology in AD, focusing on the role of Toll-like receptors and NOD-like receptor protein 3 (NLRP3) inflammasome activation in microglial cells.”,”DOI”:”10.1007/s00702-017-1831-7″,”ISSN”:”0300-9564, 1435-1463″,”journalAbbreviation”:”J Neural Transm”,”language”:”en”,”author”:{“family”:”Dansokho”,”given”:”Cira”},{“family”:”Heneka”,”given”:”Michael Thomas”},”issued”:{“date-parts”:”2017″,12,22}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Dansokho and Heneka, 2017). According to ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”TzO4zOJp”,”properties”:{“formattedCitation”:”(Baufeld et al., 2017)”,”plainCitation”:”(Baufeld et al., 2017)”,”noteIndex”:0},”citationItems”:{“id”:130,”uris”:”http://zotero.org/users/local/izdntZkG/items/5IMFLK93″,”uri”:”http://zotero.org/users/local/izdntZkG/items/5IMFLK93″,”itemData”:{“id”:130,”type”:”article-journal”,”title”:”Differential contribution of microglia and monocytes in neurodegenerative diseases”,”container-title”:”Journal of Neural Transmission”,”page”:”1-18″,”source”:”link.springer.com”,”abstract”:”Neuroinflammation is a hallmark of neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Microglia, the innate immune cells of the CNS, are the first to react to pathological insults. However, multiple studies have also demonstrated an involvement of peripheral monocytes in several neurodegenerative diseases. Due to the different origins of these two cell types, it is important to distinguish their role and function in the development and progression of these diseases. In this review, we will summarize and discuss the current knowledge of the differential contributions of microglia and monocytes in the common neurodegenerative diseases AD, PD, and ALS, as well as multiple sclerosis, which is now regarded as a combination of inflammatory processes and neurodegeneration. Until recently, it has been challenging to differentiate microglia from monocytes, as there were no specific markers. Therefore, the recent identification of specific molecular signatures of both cell types will help to advance our understanding of their differential contribution in neurodegenerative diseases.”,”DOI”:”10.1007/s00702-017-1795-7″,”ISSN”:”0300-9564, 1435-1463″,”journalAbbreviation”:”J Neural Transm”,”language”:”en”,”author”:{“family”:”Baufeld”,”given”:”Caroline”},{“family”:”O’Loughlin”,”given”:”Elaine”},{“family”:”Calcagno”,”given”:”Narghes”},{“family”:”Madore”,”given”:”Charlotte”},{“family”:”Butovsky”,”given”:”Oleg”},”issued”:{“date-parts”:”2017″,10,23}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} Baufeld et al. (2017) microglia is the first to respond to the pathological insult. Microglia is an innate immune cell of the CNS. Besides, microglia cellular response and neuroinflammation can be considered because of their neurotoxicity of environment agents. This is because the interactions between nervous system and immune, are quickly assuming big roles in injury and other neurodegenerative diseases. However, current study now is believed that the precise nature of that responses can be very differ with each type of interaction and insult. The current research shows that neuroinflammation and related cellular response of microglia are being contemplate because of the contribution to neurotoxicity of environmental agents ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”ElTvHijz”,”properties”:{“formattedCitation”:”(Harry and Kraft, 2008)”,”plainCitation”:”(Harry and Kraft, 2008)”,”noteIndex”:0},”citationItems”:{“id”:281,”uris”:”http://zotero.org/users/local/izdntZkG/items/W2ZBRETG”,”uri”:”http://zotero.org/users/local/izdntZkG/items/W2ZBRETG”,”itemData”:{“id”:281,”type”:”article-journal”,”title”:”Neuroinflammation and Microglia: Considerations and approaches for neurotoxicity assessment”,”container-title”:”Expert opinion on drug metabolism ; toxicology”,”page”:”1265-1277″,”volume”:”4″,”issue”:”10″,”source”:”PubMed Central”,”abstract”:”Background
The impact of an inflammatory response, as well as interactions between the immune and nervous systems, are rapidly assuming major roles in neurodegenerative disease and injury. However, it is now appreciated that the exact nature of such responses can differ with each type of insult and interaction. More recently, neuroinflammation and the associated cellular response of microglia are being considered for their contribution to neurotoxicity of environmental agents; yet, to date, the inclusion of inflammatory endpoints into neurotoxicity assessment have relied primarily on relatively limited measures or driven by in vitro models of neurotoxicity.

Objective
To present background information on relevant biological considerations of neuroinflammation and the microglia response demonstrating the complex integrative nature of these biological processes and raising concern with regards to translation of effects demonstrated in vitro to the in vivo situation. Specific points are addressed that would influence the design and interpretation of neuroinflammation with regards to neurotoxicology assessment.

Conclusion
There is a complex and dynamic response in the brain to regulate inflammatory processes and maintain a normal homeostatic level. The classification of such responses as beneficial or detrimental is an oversimplification. Neuroinflammation should be considered as a balanced network of processes where subtle modifications can shift the cells toward disparate outcomes. The tendency to over-interpret data obtained in an isolated culture system should be discouraged. Rather, the use of cross-disciplinary approaches to evaluate multiple endpoints should be incorporated into the assessment of inflammatory contributions to the neurotoxicity of environmental exposures.”,”DOI”:”10.1517/17425255.4.10.1265″,”ISSN”:”1742-5255″,”note”:”PMID: 18798697
PMCID: PMC2658618″,”shortTitle”:”Neuroinflammation and Microglia”,”journalAbbreviation”:”Expert Opin Drug Metab Toxicol”,”author”:{“family”:”Harry”,”given”:”G. Jean”},{“family”:”Kraft”,”given”:”Andrew D.”},”issued”:{“date-parts”:”2008″,10}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Harry and Kraft, 2008). Therefore, the understanding role of neuroinflammation is tremendously important as we can develop more efficient therapeutic strategies such. N-Palmitoylethanolamine-oxazoline is one of the example of therapeutic strategies in order to prevent neuroinflammation (Daniela et al., 2017).

2.4Neurotoxicity
According to the National Institute of Neurological Disorders and Stroke (2017), neurotoxicity is an event that occurs when the brain is exposed to natural or manmade toxic substances such as neurotoxicants that altered the whole normal activity of the CNS. These toxins can disrupt the CNS thus will kill the neurons in CNS. Neurotoxicity can also be defined as unfavorable effect on role or structure of CNS when it is induced in the by influences of chemical and physical ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”whL6zymC”,”properties”:{“formattedCitation”:”(Costa et al., 2011)”,”plainCitation”:”(Costa et al., 2011)”,”noteIndex”:0},”citationItems”:{“id”:309,”uris”:”http://zotero.org/users/local/izdntZkG/items/8G62JD2V”,”uri”:”http://zotero.org/users/local/izdntZkG/items/8G62JD2V”,”itemData”:{“id”:309,”type”:”chapter”,”title”:”Chapter 13 – In vitro approaches to developmental neurotoxicity”,”container-title”:”Reproductive and Developmental Toxicology”,”publisher”:”Academic Press”,”publisher-place”:”San Diego”,”page”:”159-166″,”source”:”ScienceDirect”,”event-place”:”San Diego”,”abstract”:”In recent years, the need to develop acceptable alternatives to conventional animal testing for neurotoxicity and developmental neurotoxicity has been increasingly recognized. Hence efforts are being directed toward the development of alternative models, utilizing either mammalian cells in culture or non-mammalian model systems. Such in vitro testing procedures have the purposes of investigating mode and/or mechanism of action of chemicals, particularly related to early, upstream events in the neurotoxic process, and of screening chemicals of unknown toxicity to flag compounds for further in vitro and in vivo neurotoxicity studies. Several cell culture models exist, with different levels of complexity, and the endpoints of toxicity to be measured remain a major issue of debate. Screening for developmental neurotoxicity may require additional specific endpoints. Promising non-mammalian models include zebrafish and C. elegans. These issues are discussed in this chapter, together with considerations for further developments and validation of alternative models.
Publisher Summary
This chapter discusses the in vitro approaches to developmental neurotoxicity. Neurotoxicity can be defined as any adverse effect on the chemistry, structure or function of the nervous system, induced by chemical or physical influences. A substance is defined as neurotoxic when it or its metabolites produce adverse effects as a result of direct interactions with the nervous system. The specific effects of the chemical on the nervous system can be detected in the course of standard toxicity testing such as developmental neurotoxicity (DNT) testing. The development of alternative in vitro models such as mammalian cells in culture or non-mammalian model systems could serve as tools for neurotoxicity and developmental neurotoxicity testing. Several issues need to be considered while choosing the mammalian cells in culture model for neurotoxicity testing such as limited lifespan, variability among different cultures, problems of purity and the need of particular attention during preparation and culturing etc. However, the in vitro systems are amenable and very useful for mechanistic studies at the cellular and molecular level and also provide a rapid, relatively inexpensive, and reliable way for screening chemicals for potential neurotoxicity and/or developmental neurotoxicity. A number of alternative non-mammalian models such as Zebrafish and C. elegans have been used to assess environmental toxicity. Finally, a battery of alternative testing models for neurotoxicity is not expected to fully replace current in vivo animal testing without efforts by regulatory agencies, institutions, foundations and private entities worldwide.”,”URL”:”https://www.sciencedirect.com/science/article/pii/B978012382032710013X”,”ISBN”:”978-0-12-382032-7″,”note”:”DOI: 10.1016/B978-0-12-382032-7.10013-X”,”author”:{“family”:”Costa”,”given”:”Lucio G.”},{“family”:”Giordano”,”given”:”Gennaro”},{“family”:”Guizzetti”,”given”:”Marina”},”editor”:{“family”:”Gupta”,”given”:”Ramesh C.”},”issued”:{“date-parts”:”2011″},”accessed”:{“date-parts”:”2018″,4,22}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Costa et al., 2011). Moreover, neurotoxicity can be considered as the source of neurodegenerative disease ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”bcn2hC0T”,”properties”:{“formattedCitation”:”(Mohammad Ahmadi Soleimani et al., 2016)”,”plainCitation”:”(Mohammad Ahmadi Soleimani et al., 2016)”,”noteIndex”:0},”citationItems”:{“id”:136,”uris”:”http://zotero.org/users/local/izdntZkG/items/C8GVKBGC”,”uri”:”http://zotero.org/users/local/izdntZkG/items/C8GVKBGC”,”itemData”:{“id”:136,”type”:”chapter”,”title”:”Chapter 2 – Drug-induced neurotoxicity in addiction medicine: From prevention to harm reduction”,”container-title”:”Progress in Brain Research”,”collection-title”:”Neuroscience for Addiction Medicine: From Prevention to Rehabilitation – Constructs and Drugs”,”publisher”:”Elsevier”,”page”:”19-41″,”volume”:”223″,”source”:”ScienceDirect”,”abstract”:”Neurotoxicity is considered as a major cause of neurodegenerative disorders. Most drugs of abuse have nonnegligible neurotoxic effects many of which are primarily mediated by several dopaminergic and glutamatergic neurotransmitter systems. Although many researchers have investigated the medical and cognitive consequences of drug abuse, the neurotoxicity induced by these drugs still requires comprehensive attention. The science of neurotoxicity promises to improve preventive and therapeutic strategies for brain disorders such as Alzheimer disease and Parkinson’s disease. However, its clinical applications for addiction medicine remain to be defined adequately. This chapter reviews the most commonly discussed mechanisms underlying neurotoxicity induced by common drugs of abuse including amphetamines, cocaine, opiates, and alcohol. In addition, the known factors that trigger and/or predispose to drug-induced neurotoxicity are discussed. These factors include drug-related, individual-related, and environmental insults. Moreover, we introduce some of the potential pharmacological antineurotoxic interventions deduced from experimental animal studies. These interventions involve various targets such as dopaminergic system, mitochondria, cell death signaling, and NMDA receptors, among others. We conclude the chapter with a discussion of addicted patients who might benefit from such interventions.”,”URL”:”http://www.sciencedirect.com/science/article/pii/S0079612315001107″,”note”:”DOI: 10.1016/bs.pbr.2015.07.004″,”shortTitle”:”Chapter 2 – Drug-induced neurotoxicity in addiction medicine”,”author”:{“family”:”Mohammad Ahmadi Soleimani”,”given”:”S.”},{“family”:”Ekhtiari”,”given”:”Hamed”},{“family”:”Cadet”,”given”:”Jean Lud”},”editor”:{“family”:”Ekhtiari”,”given”:”Hamed”},{“family”:”Paulus”,”given”:”Martin”},”issued”:{“date-parts”:”2016″,1,1},”accessed”:{“date-parts”:”2018″,4,7}},”locator”:”2″},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Mohammad et al., 2016). One of the examples of neurotoxic substances is glutamate. However, it can only become neurotoxic if the level of glutamate is in excess. The mechanism of glutamate neurotoxicity is via stimulation of N-methyl-D-aspartate receptor in which it can induce neuronal injury and death. One of the inhibitors that can protect neuronal cells from the excessive glutamate neurotoxicity is therapeutic acetylcholinesterase (AChE) inhibitor. Currently, this type of inhibitor is use to treat patient with AD ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”IwBueNJZ”,”properties”:{“formattedCitation”:”(Akaike et al., 2010)”,”plainCitation”:”(Akaike et al., 2010)”,”noteIndex”:0},”citationItems”:{“id”:138,”uris”:”http://zotero.org/users/local/izdntZkG/items/4N8GGUWM”,”uri”:”http://zotero.org/users/local/izdntZkG/items/4N8GGUWM”,”itemData”:{“id”:138,”type”:”article-journal”,”title”:”Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of ?4 and ?7 Receptors in Neuroprotection”,”container-title”:”Journal of Molecular Neuroscience”,”page”:”211-216″,”volume”:”40″,”issue”:”1-2″,”source”:”link.springer.com”,”abstract”:”Neurotoxicity induced by glutamate and other excitatory amino acids has been implicated in various neurodegenerative disorders including hypoxic ischemic events, trauma, and Alzheimer’s and Parkinson’s diseases. We examined the roles of nicotinic acetylcholine receptors (nAChRs) in survival of CNS neurons during excitotoxic events. Nicotine as well as other nicotinic receptor agonists protected cortical neurons against glutamate neurotoxicity via ?4 and ?7 nAChRs at least partly by inhibiting the process of apoptosis in near-pure neuronal cultures obtained from the cerebral cortex of fetal rats. Donepezil, galanatamine and tacrine, therapeutic acetylcholinesterase (AChE) inhibitors currently being used for treatment of Alzheimer’s disease also protected neuronal cells from glutamate neurotoxicity. Protective effects of nicotine and the AChE inhibitors were antagonized by nAChR antagonists. Moreover, nicotine and those AChE inhibitors induced up-regulation of nAChRs. Inhibitors for a non-receptor-type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galantamine. Furthermore, a phosphatidylinositol 3-kinase (PI3K) inhibitor also suppressed the neuroprotective effect of the AChE inhibitors. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galantamine treatments. These results suggest that nicotine as well as AChE inhibitors, donepezil and galantamine, prevent glutamate neurotoxicity through ?4 and ?7 nAChRs and the PI3K-Akt pathway.”,”DOI”:”10.1007/s12031-009-9236-1″,”ISSN”:”0895-8696, 1559-1166″,”shortTitle”:”Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors”,”journalAbbreviation”:”J Mol Neurosci”,”language”:”en”,”author”:{“family”:”Akaike”,”given”:”Akinori”},{“family”:”Takada-Takatori”,”given”:”Yuki”},{“family”:”Kume”,”given”:”Toshiaki”},{“family”:”Izumi”,”given”:”Yasuhiko”},”issued”:{“date-parts”:”2010″,1,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Akaike et al., 2010).

2.5Cytotoxicity
Cytotoxicity is the ability of the chemicals to damage or kill the cells by toxins and can be used as a possible treatment to treat certain type of tumors or cancers. However, cytotoxic agent can also inhibit the cells that are actively which is cell proliferation in tumors. Therefore, the cells viability can be seen after exposure to the cytotoxic agents ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”O0rpqDNF”,”properties”:{“formattedCitation”:”(Akaike et al., 2010)”,”plainCitation”:”(Akaike et al., 2010)”,”noteIndex”:0},”citationItems”:{“id”:138,”uris”:”http://zotero.org/users/local/izdntZkG/items/4N8GGUWM”,”uri”:”http://zotero.org/users/local/izdntZkG/items/4N8GGUWM”,”itemData”:{“id”:138,”type”:”article-journal”,”title”:”Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of ?4 and ?7 Receptors in Neuroprotection”,”container-title”:”Journal of Molecular Neuroscience”,”page”:”211-216″,”volume”:”40″,”issue”:”1-2″,”source”:”link.springer.com”,”abstract”:”Neurotoxicity induced by glutamate and other excitatory amino acids has been implicated in various neurodegenerative disorders including hypoxic ischemic events, trauma, and Alzheimer’s and Parkinson’s diseases. We examined the roles of nicotinic acetylcholine receptors (nAChRs) in survival of CNS neurons during excitotoxic events. Nicotine as well as other nicotinic receptor agonists protected cortical neurons against glutamate neurotoxicity via ?4 and ?7 nAChRs at least partly by inhibiting the process of apoptosis in near-pure neuronal cultures obtained from the cerebral cortex of fetal rats. Donepezil, galanatamine and tacrine, therapeutic acetylcholinesterase (AChE) inhibitors currently being used for treatment of Alzheimer’s disease also protected neuronal cells from glutamate neurotoxicity. Protective effects of nicotine and the AChE inhibitors were antagonized by nAChR antagonists. Moreover, nicotine and those AChE inhibitors induced up-regulation of nAChRs. Inhibitors for a non-receptor-type tyrosine kinase, Fyn, and janus-activated kinase 2, suppressed the neuroprotective effect of donepezil and galantamine. Furthermore, a phosphatidylinositol 3-kinase (PI3K) inhibitor also suppressed the neuroprotective effect of the AChE inhibitors. The phosphorylation of Akt, an effector of PI3K, and the expression level of Bcl-2, an anti-apoptotic protein, increased with donepezil and galantamine treatments. These results suggest that nicotine as well as AChE inhibitors, donepezil and galantamine, prevent glutamate neurotoxicity through ?4 and ?7 nAChRs and the PI3K-Akt pathway.”,”DOI”:”10.1007/s12031-009-9236-1″,”ISSN”:”0895-8696, 1559-1166″,”shortTitle”:”Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors”,”journalAbbreviation”:”J Mol Neurosci”,”language”:”en”,”author”:{“family”:”Akaike”,”given”:”Akinori”},{“family”:”Takada-Takatori”,”given”:”Yuki”},{“family”:”Kume”,”given”:”Toshiaki”},{“family”:”Izumi”,”given”:”Yasuhiko”},”issued”:{“date-parts”:”2010″,1,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Akaike et al., 2010). For example, Azathioprine, Methotrexate and Cyclophosphamide are examples of cytotoxic drugs.

2.5.1Hydrogen Peroxide
Hydrogen peroxide or H2O2 is a highly reactive agent. One of the characteristics of hydrogen peroxide is that it can react under specific conditions with a diversity of cellular components. Therefore, the reaction occurs under absence of oxygen or also can be known as anaerobic condition. Thus, the hydrogen peroxide will be converted into water (H2O) and oxygen (O2). There are a number of experiments being carried out to prove that hydrogen peroxide can destroy cancer cell without developing the dangerous by-products ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”4GcC1LAy”,”properties”:{“formattedCitation”:”(Symons et al., 2001)”,”plainCitation”:”(Symons et al., 2001)”,”noteIndex”:0},”citationItems”:{“id”:140,”uris”:”http://zotero.org/users/local/izdntZkG/items/XI4IJ6ZL”,”uri”:”http://zotero.org/users/local/izdntZkG/items/XI4IJ6ZL”,”itemData”:{“id”:140,”type”:”article-journal”,”title”:”Hydrogen peroxide: a potent cytotoxic agent effective in causing cellular damage and used in the possible treatment for certain tumours”,”container-title”:”Medical Hypotheses”,”page”:”56-58″,”volume”:”57″,”issue”:”1″,”source”:”ScienceDirect”,”abstract”:”H2O2, a highly reactive agent, can react under certain conditions with a variety of cellular components. These reactions include the lipid peroxidation of membrane and hydroxylation of proteins and DNA. The reactions can take place in the presence of oxygen and are fairly rapid, the H2O2being converted to water and oxygen. Experiments were carried out in vitro to assess the ability of this agent to destroy cancer cells without generating dangerous by-products. The direct administration of aqueous H2O2into solid tumours has the potential to cause tumour cell death. The efficacy of the use of H2O2for treating ‘solid’ cancers will necessitate its delivery to the tumour site, for example by direct special multiple injection of H2O2into a detectable tumour mass. We anticipate that, if suggested mode of delivery can be obtained, H2O2can act as an anti-cancer drug with two distinct advantages over conventional chemotherapeutic agents: to produce minimal short-?and long-term side-effects and is relatively cheap and cost effective.”,”DOI”:”10.1054/mehy.2000.1406″,”ISSN”:”0306-9877″,”shortTitle”:”Hydrogen peroxide”,”journalAbbreviation”:”Medical Hypotheses”,”author”:{“family”:”Symons”,”given”:”M. C. R.”},{“family”:”Rusakiewicz”,”given”:”S.”},{“family”:”Rees”,”given”:”R. C.”},{“family”:”Ahmad”,”given”:”S. I.”},”issued”:{“date-parts”:”2001″,7,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Symons et al., 2001). Moreover, production of H2O2 also can be found in beverage such as green tea and coffee. Thus, level of H2O2 can also be examined in the extraction of herbs such as herbal tea. Based on the research, the H2O2 in the herbal tea when prepare with hot water is only very small amount. However, the amount of H2O2 increases during the incubation at 25 °C with phosphate buffer at pH 7.4 ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”WeATzr7C”,”properties”:{“formattedCitation”:”(Aoshima et al., 2007)”,”plainCitation”:”(Aoshima et al., 2007)”,”noteIndex”:0},”citationItems”:{“id”:288,”uris”:”http://zotero.org/users/local/izdntZkG/items/IKXLG9V5″,”uri”:”http://zotero.org/users/local/izdntZkG/items/IKXLG9V5″,”itemData”:{“id”:288,”type”:”article-journal”,”title”:”Antioxidative and anti-hydrogen peroxide activities of various herbal teas”,”container-title”:”Food Chemistry”,”page”:”617-622″,”volume”:”103″,”issue”:”2″,”source”:”ScienceDirect”,”abstract”:”Herbal teas, i.e., extracts of herbs, are popular because of their fragrance and antioxidative activity. Since the antioxidative activity comes mainly from polyphenols, total polyphenol concentrations and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities in herbal teas were measured and compared. Levels of H2O2 in the teas were also examined, since the production of H2O2 in beverages such as coffee and green tea, has been reported. Only a small amount of H2O2 was detected in the herbal teas just after their preparation with hot water. However, H2O2 was gradually produced during incubation at 25°C after extraction with hot water, especially when the teas were incubated in phosphate buffer at pH 7.4. To examine the anti-H2O2 activity of herbal teas, various teas were added to a catechin-enriched green tea, which produce much H2O2, and they were incubated at 25°C for one day. Addition of hibiscus and thorn apple tea decreased the production of H2O2 in the catechin-enriched green tea, possibly because of a lowering of the pH of the mixture.”,”DOI”:”10.1016/j.foodchem.2006.08.032″,”ISSN”:”0308-8146″,”journalAbbreviation”:”Food Chemistry”,”author”:{“family”:”Aoshima”,”given”:”H.”},{“family”:”Hirata”,”given”:”S.”},{“family”:”Ayabe”,”given”:”S.”},”issued”:{“date-parts”:”2007″,1,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Aoshima et al., 2007).

2.6Herbal medicines
Herbal medicines is a plant-derives substances which can be used to treat many illnesses and diseases because they are naturally occurring. They are composed of mixtures of organic chemicals that can be found in part of the plant. Throughout these years, the researchers have been concentrating on medicinal herbs because of its large range of pharmacological significance ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”qAp5v4jE”,”properties”:{“formattedCitation”:”(Shukla et al., 2010)”,”plainCitation”:”(Shukla et al., 2010)”,”noteIndex”:0},”citationItems”:{“id”:145,”uris”:”http://zotero.org/users/local/izdntZkG/items/R4AKDYCL”,”uri”:”http://zotero.org/users/local/izdntZkG/items/R4AKDYCL”,”itemData”:{“id”:145,”type”:”article-journal”,”title”:”Studies on anti-inflammatory, antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models”,”container-title”:”Food and Chemical Toxicology”,”page”:”61-64″,”volume”:”48″,”issue”:”1″,”source”:”ScienceDirect”,”abstract”:”Caesalpinia bonducella FLEMING (Caesalpiniaceae) plant is well known for its medicinal and therapeutic values in Indian Ayurveda. However, to be clinically useful, more scientific data are needed. Therefore, in the present study, we investigated the effects of C. bonducella seed oil on acute and chronic inflammation. To assess the anti-inflammatory, antipyretic and analgesic activities, varied concentrations of the seed oil of C. bonducella (100, 200 and 400mg/kg orally) were tested in carrageenan-induced rat paw oedema, brewer’s yeast-induced pyrexia, acetic acid-induced writhing and hot plate reaction time in experimental rats. The paw volumes, pyrexia and writhes in experimental rats were reduced significantly (p;0.05) as compared to that of control, and hot plate test showed significant licking effect in rats. These results clearly indicate that the oil of C. bonducella seeds could be a potential source for using as anti-inflammatory, antipyretic and analgesic agent.”,”DOI”:”10.1016/j.fct.2009.09.015″,”ISSN”:”0278-6915″,”journalAbbreviation”:”Food and Chemical Toxicology”,”author”:{“family”:”Shukla”,”given”:”Shruti”},{“family”:”Mehta”,”given”:”Archana”},{“family”:”Mehta”,”given”:”Pradeep”},{“family”:”Vyas”,”given”:”Suresh Prasad”},{“family”:”Shukla”,”given”:”Savita”},{“family”:”Bajpai”,”given”:”Vivek K.”},”issued”:{“date-parts”:”2010″,1,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Shukla et al., 2010). The traditional medicines have become a very popular healthcare worldwide because of the practices based on theories, beliefs and experiences of different culture. However, not all herbal medicines are safe. Sometimes, it can bring risks and harm to someone. Therefore, herbal medicine should be tested using conventional trial procedure ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”NVIRPpXs”,”properties”:{“formattedCitation”:”(Firenzuoli and Gori, 2007)”,”plainCitation”:”(Firenzuoli and Gori, 2007)”,”noteIndex”:0},”citationItems”:{“id”:147,”uris”:”http://zotero.org/users/local/izdntZkG/items/V34TYR4Y”,”uri”:”http://zotero.org/users/local/izdntZkG/items/V34TYR4Y”,”itemData”:{“id”:147,”type”:”article-journal”,”title”:”Herbal Medicine Today: Clinical and Research Issues”,”container-title”:”Evidence-based Complementary and Alternative Medicine : eCAM”,”page”:”37-40″,”volume”:”4″,”issue”:”Suppl 1″,”source”:”PubMed Central”,”abstract”:”Herbal medicine is the use of medicinal plants for prevention and treatment of diseases: it ranges from traditional and popular medicines of every country to the use of standardized and tritated herbal extracts. Generally cultural rootedness enduring and widespread use in a Traditional Medical System may indicate safety, but not efficacy of treatments, especially in herbal medicine where tradition is almost completely based on remedies containing active principles at very low and ultra low concentrations, or relying on magical-energetic principles., In the age of globalization and of the so-called ‘plate world’, assessing the ‘transferability’ of treatments between different cultures is not a relevant goal for clinical research, while are the assessment of efficacy and safety that should be based on the regular patterns of mainstream clinical medicine., The other black box of herbal-based treatments is the lack of definite and complete information about the composition of extracts. Herbal derived remedies need a powerful and deep assessment of their pharmacological qualities and safety that actually can be realized by new biologic technologies like pharmacogenomic, metabolomic and microarray methology. Because of the large and growing use of natural derived substances in all over the world, it is not wise to rely also on the tradition or supposed millenarian beliefs; explanatory and pragmatic studies are useful and should be considered complementary in the acquisition of reliable data both for health caregiver and patients.”,”DOI”:”10.1093/ecam/nem096″,”ISSN”:”1741-427X”,”note”:”PMID: 18227931
PMCID: PMC2206236″,”shortTitle”:”Herbal Medicine Today”,”journalAbbreviation”:”Evid Based Complement Alternat Med”,”author”:{“family”:”Firenzuoli”,”given”:”Fabio”},{“family”:”Gori”,”given”:”Luigi”},”issued”:{“date-parts”:”2007″,9}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Firenzuoli and Gori, 2007). There are various studies that herbal medicine can be used to treat neurodegenerative symptoms. This is because of the phytochemicals from plants can maintain or enhance the brain function. There are many phytochemicals substances such as fatty acid, flavonoid, curcumin and phenols that is important to neuroprotective function. Cantella asiatica or also known as “daun pegaga” in Malaysia is proven to reduce the oxidative stress parameters.

Figure 2.1: Asiatic acid, madecassic acid, asiaticoside and madecassoside from Centella asiatica ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”dydF3kUE”,”properties”:{“formattedCitation”:”(Kumar and Khanum, 2012)”,”plainCitation”:”(Kumar and Khanum, 2012)”,”noteIndex”:0},”citationItems”:{“id”:21,”uris”:”http://zotero.org/users/local/izdntZkG/items/B5UX649U”,”uri”:”http://zotero.org/users/local/izdntZkG/items/B5UX649U”,”itemData”:{“id”:21,”type”:”article-journal”,”title”:”Neuroprotective potential of phytochemicals”,”container-title”:”Pharmacognosy Reviews”,”page”:”81-90″,”volume”:”6″,”issue”:”12″,”source”:”PubMed”,”abstract”:”Cognitive dysfunction is a major health problem in the 21st century, and many neuropsychiatric disorders and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer’s Disease dementia, cerebrovascular impairment, seizure disorders, head injury and Parkinsonism, can be severly functionally debilitating in nature. In course of time, a number of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well newer molecules have been tried against these targets. Phytochemicals from medicinal plants play a vital role in maintaining the brain’s chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional practice of medicine, several plants have been reported to treat cognitive disorders. In this review paper, we attempt to throw some light on the use of medicinal herbs to treat cognitive disorders. In this review, we briefly deal with some medicinal herbs focusing on their neuroprotective active phytochemical substances like fatty acids, phenols, alkaloids, flavonoids, saponins, terpenes etc. The resistance of neurons to various stressors by activating specific signal transduction pathways and transcription factors are also discussed. It was observed in the review that a number of herbal medicines used in Ayurvedic practices as well Chinese medicines contain multiple compounds and phytochemicals that may have a neuroprotective effect which may prove beneficial in different neuropsychiatric and neurodegenerative disorders. Though the presence of receptors or transporters for polyphenols or other phytochemicals of the herbal preparations, in brain tissues remains to be ascertained, compounds with multiple targets appear as a potential and promising class of therapeutics for the treatment of diseases with a multifactorial etiology.”,”DOI”:”10.4103/0973-7847.99898″,”ISSN”:”0976-2787″,”note”:”PMID: 23055633
PMCID: PMC3459459″,”journalAbbreviation”:”Pharmacogn Rev”,”language”:”eng”,”author”:{“family”:”Kumar”,”given”:”G. Phani”},{“family”:”Khanum”,”given”:”Farhath”},”issued”:{“date-parts”:”2012″,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kumar and Khanum, 2012).

Other than that, Gingko biloba contains terpenoids, flavonoids and steroids that can function to improve memory loss and abnormal blood circulations. Lastly, Ilex paraguariensis or its common name is Yerba mate can enhance the memory on dementia patient ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”JEXj3Y23″,”properties”:{“formattedCitation”:”(Kumar and Khanum, 2012)”,”plainCitation”:”(Kumar and Khanum, 2012)”,”noteIndex”:0},”citationItems”:{“id”:21,”uris”:”http://zotero.org/users/local/izdntZkG/items/B5UX649U”,”uri”:”http://zotero.org/users/local/izdntZkG/items/B5UX649U”,”itemData”:{“id”:21,”type”:”article-journal”,”title”:”Neuroprotective potential of phytochemicals”,”container-title”:”Pharmacognosy Reviews”,”page”:”81-90″,”volume”:”6″,”issue”:”12″,”source”:”PubMed”,”abstract”:”Cognitive dysfunction is a major health problem in the 21st century, and many neuropsychiatric disorders and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer’s Disease dementia, cerebrovascular impairment, seizure disorders, head injury and Parkinsonism, can be severly functionally debilitating in nature. In course of time, a number of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well newer molecules have been tried against these targets. Phytochemicals from medicinal plants play a vital role in maintaining the brain’s chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional practice of medicine, several plants have been reported to treat cognitive disorders. In this review paper, we attempt to throw some light on the use of medicinal herbs to treat cognitive disorders. In this review, we briefly deal with some medicinal herbs focusing on their neuroprotective active phytochemical substances like fatty acids, phenols, alkaloids, flavonoids, saponins, terpenes etc. The resistance of neurons to various stressors by activating specific signal transduction pathways and transcription factors are also discussed. It was observed in the review that a number of herbal medicines used in Ayurvedic practices as well Chinese medicines contain multiple compounds and phytochemicals that may have a neuroprotective effect which may prove beneficial in different neuropsychiatric and neurodegenerative disorders. Though the presence of receptors or transporters for polyphenols or other phytochemicals of the herbal preparations, in brain tissues remains to be ascertained, compounds with multiple targets appear as a potential and promising class of therapeutics for the treatment of diseases with a multifactorial etiology.”,”DOI”:”10.4103/0973-7847.99898″,”ISSN”:”0976-2787″,”note”:”PMID: 23055633
PMCID: PMC3459459″,”journalAbbreviation”:”Pharmacogn Rev”,”language”:”eng”,”author”:{“family”:”Kumar”,”given”:”G. Phani”},{“family”:”Khanum”,”given”:”Farhath”},”issued”:{“date-parts”:”2012″,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kumar and Khanum, 2012). However, the benefits of Syzygium polyanthum towards the neurodegenerative disease are not well-known yet.

2.6.1Syzygium polyanthumSyzygium polyanthum (SD) also known as bay leaf or “daun salam” is broadly used in Malaysian and Indonesian cuisine. This plant belongs to Myrtacea family and commonly used as a traditional medicine. The leaves of the plant is said to bring various benefits to human’s health. SD grows on lowlands and distributed in subtropical, temperate and tropical regions all around the world. According to ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”BJjkUTKR”,”properties”:{“formattedCitation”:”(Kusuma et al., 2011)”,”plainCitation”:”(Kusuma et al., 2011)”,”noteIndex”:0},”citationItems”:{“id”:158,”uris”:”http://zotero.org/users/local/izdntZkG/items/NKJSDKY5″,”uri”:”http://zotero.org/users/local/izdntZkG/items/NKJSDKY5″,”itemData”:{“id”:158,”type”:”article-journal”,”title”:”Biological Activity and Phytochemical Analysis of Three Indonesian Medicinal Plants, Murraya koenigii, Syzygium polyanthum and Zingiber purpurea”,”container-title”:”Journal of Acupuncture and Meridian Studies”,”page”:”75-79″,”volume”:”4″,”issue”:”1″,”source”:”www.jams-kpi.com”,”DOI”:”10.1016/S2005-2901(11)60010-1″,”ISSN”:”2005-2901″,”note”:”PMID: 21440883″,”journalAbbreviation”:”Journal of Acupuncture and Meridian Studies”,”language”:”English”,”author”:{“family”:”Kusuma”,”given”:”Irawan Wijaya”},{“family”:”Kuspradini”,”given”:”Harlinda”},{“family”:”Arung”,”given”:”Enos Tangke”},{“family”:”Aryani”,”given”:”Farida”},{“family”:”Min”,”given”:”Yu-Hong”},{“family”:”Kim”,”given”:”Jin-Sook”},{“family”:”Kim”,”given”:”Yong-ung”},”issued”:{“date-parts”:”2011″,3,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kusuma et al., 2011), SD is extracted in order to study about their biological activity. Furthermore, SD ripened fruit shows the potential to become source of cytotoxic compounds, antimicrobial and antioxidant. Besides, the antioxidant activity of the extracted SD fruits shows to be more active than other plant extracts such as M. koenigii and Z. purpurea. Next, SD leaves contain a lot of phytochemicals such as carbohydrate, tannin, alkaloid, steroid, triterpenoid and flavonoid while saponin only present in SD ripened fruits. Another research done by ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”z64obhn8″,”properties”:{“formattedCitation”:”(A et al., 2013)”,”plainCitation”:”(A et al., 2013)”,”noteIndex”:0},”citationItems”:{“id”:162,”uris”:”http://zotero.org/users/local/izdntZkG/items/39TVQI2F”,”uri”:”http://zotero.org/users/local/izdntZkG/items/39TVQI2F”,”itemData”:{“id”:162,”type”:”article-journal”,”title”:”Chemical Composition, Antioxidant and Antibacterial Activities of Syzygium Polyanthum (Wight) Walp. Essential Oils”,”container-title”:”The Open Conference Proceedings Journal”,”volume”:”4″,”issue”:”1″,”source”:”benthamopen.com”,”abstract”:”Chemical Composition, Antioxidant and Antibacterial Activities of Syzygium Polyanthum (Wight) Walp. Essential Oils”,”URL”:”https://benthamopen.com/ABSTRACT/TOPROCJ-4-4-139″,”author”:{“family”:”A”,”given”:”Amalina”},{“family”:”Nur”,”given”:””},{“family”:”G”,”given”:”Natanamurugaraj”},{“family”:”My”,”given”:”Mashitah”},{“family”:”Ak”,”given”:”Ashikin”},{“family”:”Nurul”,”given”:””},”issued”:{“date-parts”:”2013″,3,1},”accessed”:{“date-parts”:”2018″,4,8}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} Amalina et al. (2013), the essential oil from SD leaves were extracted. The result shows that SD essential oils can be part of development of new natural-based products. Other than that, SD ethanolic extract is proved to be antioxidant agent and anti-hypoglycemic thus effective for the treatment of Diabetes Mellitus or hyperglycemia. This plant is popular because of its function which helps lower the blood sugar level in our body ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”TzcBN5ZU”,”properties”:{“formattedCitation”:”(Situmorang et al., 2015)”,”plainCitation”:”(Situmorang et al., 2015)”,”noteIndex”:0},”citationItems”:{“id”:167,”uris”:”http://zotero.org/users/local/izdntZkG/items/PYXMQTX7″,”uri”:”http://zotero.org/users/local/izdntZkG/items/PYXMQTX7″,”itemData”:{“id”:167,”type”:”article-journal”,”title”:”KARO’S LOCAL WISDOM: THE USE OF WOODY PLANTS FOR TRADITIONAL DIABETIC MEDICINES”,”container-title”:”Indonesian Journal of Forestry Research”,”page”:”121-130″,”volume”:”2″,”issue”:”2″,”source”:”ejournal.forda-mof.org”,”abstract”:”This paper identifies the plant species used  traditionally by Karo people in North Sumatra, to cure diabetes, analyses the cultural significance index of  those plants for the Karo, and clarifies phytochemical contents of  the plants. Data were collected using survey method from selected respondents (n=54) based on their knowledge and practices in utilising medicinal plants to cure diabetic disease. Index of  Cultural Significance (ICS) of  plants was determined using the method proposed by Turner. Results showed that twelve woody plant species have been used to cure diabetes: loning leave (Psychotria sp.), kacihe leave (Prunus accuminta Hook), umbrella tree leave (Maesopsis eminii Engl), mutamba leave (Guazuma ulmifolia Lamk), cepcepan leave (Villebrunea subescens Blume), pirdot/cepcepan lembu leave (Saurauia vulcani Korth), raru bark (Cotylelobium melanoxylo), breadfruit leave (Artocarpus altilis), salam leave (Syzygium polyanthum Wight), mahogany seed (Swietenia mahagoni (L.) Jacq), cinnamon bark (Cinnamomum burmani), and yellow bamboo rod (Bambusa vulgaris Schrad). Five of  those plants: loning, umbrella tree, mutamba, raru and salam have the highest cultural significance level. These five plants are highly needed in large quatities by the Karo people, so their availability in the forest should be securely conserved and protected. The plants used contained alkaloids, flavonoids, phenolics and terpenoids which can help to lower blood sugar level.”,”DOI”:”10.20886/ijfr.2015.2.2.121-130″,”ISSN”:”2406-8195″,”shortTitle”:”KARO’S LOCAL WISDOM”,”language”:”en”,”author”:{“family”:”Situmorang”,”given”:”Rospita Odorlina”},{“family”:”Harianja”,”given”:”Alfonsus H.”},{“family”:”Silalahi”,”given”:”Johansen”},”issued”:{“date-parts”:”2015″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Situmorang et al., 2015). Therefore, the phytochemicals contains in plant extract can be applied not only to cell line but also to the animal model for future investigations ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”Y4LNDzmr”,”properties”:{“formattedCitation”:”(Bathaie et al., 2015)”,”plainCitation”:”(Bathaie et al., 2015)”,”noteIndex”:0},”citationItems”:{“id”:293,”uris”:”http://zotero.org/users/local/izdntZkG/items/LE5PP828″,”uri”:”http://zotero.org/users/local/izdntZkG/items/LE5PP828″,”itemData”:{“id”:293,”type”:”chapter”,”title”:”Chapter One – How Phytochemicals Prevent Chemical Carcinogens and/or Suppress Tumor Growth?”,”container-title”:”The Enzymes”,”collection-title”:”Mechanism of the Anticancer Effect of Phytochemicals”,”publisher”:”Academic Press”,”page”:”1-42″,”volume”:”37″,”source”:”ScienceDirect”,”abstract”:”Phytochemicals are a powerful group of chemicals that are derived from natural resource, especially with plants origin. They have shown to exhibit chemoprevention and chemotherapeutic effects not only in cell lines and in animal models of cancer but also some of them are in the clinical trial phase I and II. Despite numerous reports of these phytochemical effects on cancer, an overview of the mechanisms of their action and their effects on various cellular and molecular functions important in the inhibition of cancer progression has been lacking. In this review, we attempt to catalogue various studies to examine the effect of phytochemicals in cancer initiation, promotion, signaling, and epigenetic changes. Because of the numerous studies in these topics, we only pointed out to some examples in each section.”,”URL”:”http://www.sciencedirect.com/science/article/pii/S1874604715000098″,”note”:”DOI: 10.1016/bs.enz.2015.06.003″,”author”:{“family”:”Bathaie”,”given”:”S. Zahra”},{“family”:”Faridi”,”given”:”Nasim”},{“family”:”Nasimian”,”given”:”Ahmad”},{“family”:”Heidarzadeh”,”given”:”Hamid”},{“family”:”Tamanoi”,”given”:”Fuyuhiko”},”editor”:{“family”:”Bathaie”,”given”:”S. Zahra”},{“family”:”Tamanoi”,”given”:”Fuyuhiko”},”issued”:{“date-parts”:”2015″,1,1},”accessed”:{“date-parts”:”2018″,4,22}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Bathaie et al., 2015).
2.7Animal model
Animal is widely use by researchers as a model for physiology and anatomy of human for scientific purposes ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”DtAZPRux”,”properties”:{“formattedCitation”:”(Ericsson et al., 2013)”,”plainCitation”:”(Ericsson et al., 2013)”,”noteIndex”:0},”citationItems”:{“id”:254,”uris”:”http://zotero.org/users/local/izdntZkG/items/7XB5K2S9″,”uri”:”http://zotero.org/users/local/izdntZkG/items/7XB5K2S9″,”itemData”:{“id”:254,”type”:”article-journal”,”title”:”A Brief History of Animal Modeling”,”container-title”:”Missouri medicine”,”page”:”201-205″,”volume”:”110″,”issue”:”3″,”source”:”PubMed Central”,”abstract”:”Comparative medicine is founded on the concept that other animal species share physiological, behavioral, or other characteristics with humans. Over 2,400 years ago it was recognized that by studying animals, we could learn much about ourselves. This technique has now developed to the point that animal models are employed in virtually all fields of biomedical research including, but not limited to, basic biology, immunology and infectious disease, oncology, and behavior.”,”ISSN”:”0026-6620″,”note”:”PMID: 23829102
PMCID: PMC3979591″,”journalAbbreviation”:”Mo Med”,”author”:{“family”:”Ericsson”,”given”:”Aaron C.”},{“family”:”Crim”,”given”:”Marcus J.”},{“family”:”Franklin”,”given”:”Craig L.”},”issued”:{“date-parts”:”2013″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Ericsson et al., 2013). This is because of the similarities of animals’ physiological and anatomical with human. Therefore, the researchers are prompted to study more deeply on animals’ novel therapy and mechanism before applying their findings to the human. Moreover, mice and rats are commonly used as animal model in biomedical research. Other than that, human diseases can also affect and related to many animal species such as allergies, cancer, epilepsy and Type I diabetes. The mechanism of these diseases are so identical to the point that 90% of veterinary drugs that can treat animals are similar to those that being used to treat humans. Vaccines are one of the example that being develop by using animal models. In 1921, McLeod and Banting received the Nobel Prize because of their achievement in finding the treatment of Type I diabetes by using insulin in the dog ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”fPMcGhAy”,”properties”:{“formattedCitation”:”(Barr\uc0\u233{}-Sinoussi and Montagutelli, 2015)”,”plainCitation”:”(Barré-Sinoussi and Montagutelli, 2015)”,”noteIndex”:0},”citationItems”:{“id”:251,”uris”:”http://zotero.org/users/local/izdntZkG/items/9TZKLBT2″,”uri”:”http://zotero.org/users/local/izdntZkG/items/9TZKLBT2″,”itemData”:{“id”:251,”type”:”article-journal”,”title”:”Animal models are essential to biological research: issues and perspectives”,”container-title”:”Future Science OA”,”volume”:”1″,”issue”:”4″,”source”:”future-science.com (Atypon)”,”URL”:”https://www.future-science.com/doi/full/10.4155/fso.15.63″,”DOI”:”10.4155/fso.15.63″,”shortTitle”:”Animal models are essential to biological research”,”journalAbbreviation”:”Future Science OA”,”author”:{“family”:”Barré-Sinoussi”,”given”:”Françoise”},{“family”:”Montagutelli”,”given”:”Xavier”},”issued”:{“date-parts”:”2015″,7,31},”accessed”:{“date-parts”:”2018″,4,21}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Barré-Sinoussi and Montagutelli, 2015). Various experiment on animals are being conducted with the hope of gaining new input and knowledge that can be use to humans ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”GiRX26qt”,”properties”:{“formattedCitation”:”(Sjoberg, 2017)”,”plainCitation”:”(Sjoberg, 2017)”,”noteIndex”:0},”citationItems”:{“id”:260,”uris”:”http://zotero.org/users/local/izdntZkG/items/9VHEUBPN”,”uri”:”http://zotero.org/users/local/izdntZkG/items/9VHEUBPN”,”itemData”:{“id”:260,”type”:”article-journal”,”title”:”Logical fallacies in animal model research”,”container-title”:”Behavioral and Brain Functions : BBF”,”volume”:”13″,”source”:”PubMed Central”,”abstract”:”Background
Animal models of human behavioural deficits involve conducting experiments on animals with the hope of gaining new knowledge that can be applied to humans. This paper aims to address risks, biases, and fallacies associated with drawing conclusions when conducting experiments on animals, with focus on animal models of mental illness.

Conclusions
Researchers using animal models are susceptible to a fallacy known as false analogy, where inferences based on assumptions of similarities between animals and humans can potentially lead to an incorrect conclusion. There is also a risk of false positive results when evaluating the validity of a putative animal model, particularly if the experiment is not conducted double-blind. It is further argued that animal model experiments are reconstructions of human experiments, and not replications per se, because the animals cannot follow instructions. This leads to an experimental setup that is altered to accommodate the animals, and typically involves a smaller sample size than a human experiment. Researchers on animal models of human behaviour should increase focus on mechanistic validity in order to ensure that the underlying causal mechanisms driving the behaviour are the same, as relying on face validity makes the model susceptible to logical fallacies and a higher risk of Type 1 errors. We discuss measures to reduce bias and risk of making logical fallacies in animal research, and provide a guideline that researchers can follow to increase the rigour of their experiments.”,”URL”:”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312558/”,”DOI”:”10.1186/s12993-017-0121-8″,”ISSN”:”1744-9081″,”note”:”PMID: 28202023
PMCID: PMC5312558″,”journalAbbreviation”:”Behav Brain Funct”,”author”:{“family”:”Sjoberg”,”given”:”Espen A.”},”issued”:{“date-parts”:”2017″,2,15},”accessed”:{“date-parts”:”2018″,4,21}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Sjoberg, 2017). Other than mice and rats, leeches are also popular as an animal model.

2.7.1The local leech, Hirudinaria manillensis
Hirudinaria manillensis (HM) is known as buffalo leech which is segmented invertebrate animal. Normally, HM is found in the Southeast Asia such as Malaysia, Thailand, Vietnam, Indonesia and Philippines. It is a freshwater leech that has three jaws and it belongs to family Hirudinidae ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”gelF24zf”,”properties”:{“formattedCitation”:”(Phillips and Siddall, 2009)”,”plainCitation”:”(Phillips and Siddall, 2009)”,”noteIndex”:0},”citationItems”:{“id”:176,”uris”:”http://zotero.org/users/local/izdntZkG/items/U7JSCTKF”,”uri”:”http://zotero.org/users/local/izdntZkG/items/U7JSCTKF”,”itemData”:{“id”:176,”type”:”article-journal”,”title”:”Poly-paraphyly of Hirudinidae: many lineages of medicinal leeches”,”container-title”:”BMC Evolutionary Biology”,”page”:”246″,”volume”:”9″,”source”:”BioMed Central”,”abstract”:”Medicinal leeches became infamous for their utility in bloodletting popularized in the 19th century, and have seen a recent resurgence in post-operative treatments for flap and replantation surgeries, and in terms of characterization of salivary anticoagulants. Notorious throughout the world, the quintessential leech family Hirudinidae has been taken for granted to be monophyletic, as has the non-bloodfeeding family Haemopidae.”,”DOI”:”10.1186/1471-2148-9-246″,”ISSN”:”1471-2148″,”shortTitle”:”Poly-paraphyly of Hirudinidae”,”journalAbbreviation”:”BMC Evolutionary Biology”,”author”:{“family”:”Phillips”,”given”:”Anna J.”},{“family”:”Siddall”,”given”:”Mark E.”},”issued”:{“date-parts”:”2009″,10,7}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Phillips and Siddall, 2009). It is also belongs to phylum Annelida. Normally, HM is cultured in farm as it can be used as traditional medicine ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”W8gA1G1B”,”properties”:{“formattedCitation”:”(Elliott and Kutschera, 2011)”,”plainCitation”:”(Elliott and Kutschera, 2011)”,”noteIndex”:0},”citationItems”:{“id”:180,”uris”:”http://zotero.org/users/local/izdntZkG/items/Q24NJHS2″,”uri”:”http://zotero.org/users/local/izdntZkG/items/Q24NJHS2″,”itemData”:{“id”:180,”type”:”article-journal”,”title”:”Medicinal leeches: Historical use, ecology, genetics and conservation”,”container-title”:”Freshwater Reviews”,”page”:”21-41″,”volume”:”4″,”issue”:”1″,”source”:”www.fba.org.uk”,”abstract”:”After a short introduction to the classification of medicinal leeches, their historical use in phlebotomy (blood-letting) and contemporary use in neurobiology and medicine are summarised.;nbsp; Over-collecting of wild Hirudo medicinalis in Europe led to reduced populations and the need to import other species, especially the closely related Hirudo verbana from Turkey and, more recently, the Caribbean and Asian leech, Hirudinaria manillensis.;nbsp; The limited information on the quantitative ecology of European medicinal leeches is summarised next. They require warm-water ponds with a range of suitable hosts, especially amphibians, to survive and prosper.;nbsp; Medicinal leeches can persist with a low minimum viable population size, which may be typical of rare freshwater invertebrates in isolated habitats, especially species limited by high temperature requirements and specialised food sources.;nbsp; Phylogenetic relationships, using molecular methodology, show that there are at least two independent lineages of medicinal leeches with Hirudo medicinalis, H. verbana and Hirudinaria manillensis being closely related.;nbsp; The type species, H. medicinalis, was once abundant in Europe but is now rare and on the endangered list in several countries.;nbsp; Genetic studies have confirmed the erroneous marketing of H. verbana as H. medicinalis.;nbsp; It is highly probable that H. verbana has already escaped into the wild.;nbsp; Unlike H. medicinalis, H. verbana has no legal protection.;nbsp; We conclude that the major factor in the decline of medicinal leech populations has been the general loss of wetlands, especially eutrophic ponds and marshes throughout Europe.;nbsp; Destruction of these water bodies has also led to a decline in amphibians that are an important source of blood-meals for the leeches and are crucial for the survival of their juveniles.;nbsp; More quantitative information is required on H. medicinalis, and especially H. verbana, to facilitate their conservation and management, and to prevent them becoming extinct in the wild.”,”DOI”:”10.1608/FRJ-4.1.417″,”ISSN”:”1775-084x”,”shortTitle”:”Medicinal leeches”,”language”:”en”,”author”:{“family”:”Elliott”,”given”:”Malcolm”},{“family”:”Kutschera”,”given”:”Ulrich”},”issued”:{“date-parts”:”2011″,7,18}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Elliott and Kutschera, 2011). For example, it can be used as leech therapy such as blood-sucking for many blood-related problems or disease ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”NvCBiskK”,”properties”:{“formattedCitation”:”(Bickel et al., 1994)”,”plainCitation”:”(Bickel et al., 1994)”,”noteIndex”:0},”citationItems”:{“id”:182,”uris”:”http://zotero.org/users/local/izdntZkG/items/PGM27V6Y”,”uri”:”http://zotero.org/users/local/izdntZkG/items/PGM27V6Y”,”itemData”:{“id”:182,”type”:”article-journal”,”title”:”Intestinal Flora of the Medicinal Leech Hirudinaria Manillensis”,”container-title”:”Journal of Reconstructive Microsurgery”,”page”:”83-85″,”volume”:”10″,”issue”:”02″,”source”:”www.thieme-connect.com”,”abstract”:”Thieme E-Books ; E-Journals”,”DOI”:”10.1055/s-2007-1006575″,”ISSN”:”0743-684X, 1098-8947″,”journalAbbreviation”:”J reconstr Microsurg”,”language”:”en”,”author”:{“family”:”Bickel”,”given”:”Kyle D.”},{“family”:”Lineaweaver”,”given”:”William C.”},{“family”:”Follansbee”,”given”:”Stephen”},{“family”:”Feibel”,”given”:”Robert”},{“family”:”Jackson”,”given”:”Rebecca”},{“family”:”Buncke”,”given”:”Harry J.”},”issued”:{“date-parts”:”1994″,3}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Bickel et al., 1994). Besides, leeches have their natural system which is posterior sucker. The function of the posterior sucker is that it will allow the leech to adhere to a substrate. The mechanism of adhesion in leech is a wet adhesion. This is because the surface of posterior sucker is very smooth and clear and definitely sealing can accomplished only on the wet surface ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”MlA8e95g”,”properties”:{“formattedCitation”:”(Feng et al., 2015)”,”plainCitation”:”(Feng et al., 2015)”,”noteIndex”:0},”citationItems”:{“id”:196,”uris”:”http://zotero.org/users/local/izdntZkG/items/AQZV8QD9″,”uri”:”http://zotero.org/users/local/izdntZkG/items/AQZV8QD9″,”itemData”:{“id”:196,”type”:”article-journal”,”title”:”Experimental Investigation on the Morphology and Adhesion Mechanism of Leech Posterior Suckers”,”container-title”:”PLOS ONE”,”page”:”e0140776″,”volume”:”10″,”issue”:”11″,”source”:”PLoS Journals”,”abstract”:”The posterior sucker of a leech represents a fascinating natural system that allows the leech to adhere to different terrains and substrates. However, the mechanism of adhesion and desorption has not yet to be elucidated. In order to better understand how the adhesion is performed, we analyzed the surface structure, adsorption movements, the muscles’ distribution, physical characteristics, and the adsorption force of the leech posterior suckers by experimental investigation. Three conclusions can be drawn based on the obtained experimental results. First, the adhesion by the posterior sucker is wet adhesion, because the surface of the posterior sucker is smooth and the sealing can only be achieved on wet surfaces. Second, the deformation texture, consisting of soft collagen tissues and highly ductile epidermal tissues, plays a key role in adhering to rough surfaces. Finally, the adhesion and desorption is achieved by the synergetic operation of six muscle fibers working in different directions. Concrete saying, directional deformation of the collagen/epithermal interface driven by spatially-distributed muscle fibers facilitates the excretion of fluids in the sucker venter, thus allowing liquid sealing. Furthermore, we found that the adhesion strength is directly related to the size of the contact surface which is generated and affected by the sucker deformation. Such an underlying physical mechanism offers potential cues for developing innovative bio-inspired artificial adhesion systems.”,”DOI”:”10.1371/journal.pone.0140776″,”ISSN”:”1932-6203″,”journalAbbreviation”:”PLOS ONE”,”language”:”en”,”author”:{“family”:”Feng”,”given”:”Huashan”},{“family”:”Chai”,”given”:”Ningli”},{“family”:”Dong”,”given”:”Wenhao”},”issued”:{“date-parts”:”2015″,11,4}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Feng et al., 2015). Moreover, the characteristic of leech is that it is hermaphrodite. A hermaphrodite is a condition when one individual has both female and male reproductive system. Therefore, two leeches can bent around each other to their oral suckers when mating ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”Dk6iJ3qk”,”properties”:{“formattedCitation”:”(Wagenaar, 2015)”,”plainCitation”:”(Wagenaar, 2015)”,”noteIndex”:0},”citationItems”:{“id”:204,”uris”:”http://zotero.org/users/local/izdntZkG/items/W46D4DYZ”,”uri”:”http://zotero.org/users/local/izdntZkG/items/W46D4DYZ”,”itemData”:{“id”:204,”type”:”article-journal”,”title”:”A classic model animal in the 21st century: recent lessons from the leech nervous system”,”container-title”:”Journal of Experimental Biology”,”page”:”3353-3359″,”volume”:”218″,”issue”:”21″,”source”:”jeb.biologists.org”,”abstract”:”Skip to Next Section
The medicinal leech (genus Hirudo) is a classic model animal in systems neuroscience. The leech has been central to many integrative studies that establish how properties of neurons and their interconnections give rise to the functioning of the animal at the behavioral level. Leeches exhibit several discrete behaviors (such as crawling, swimming and feeding) that are each relatively simple. Importantly, these behaviors can all be studied – at least at a basal level – in the isolated nervous system. The leech nervous system is particularly amenable to such studies because of its distributed nature; sensory processing and generation of behavior occur to a large degree in iterated segmental ganglia that each contain only ?400 neurons. Furthermore, the neurons are relatively large and are arranged with stereotyped topography on the surface of the ganglion, which greatly facilitates their identification and accessibility. This Commentary provides an overview of recent work on the leech nervous system, with particular focus on circuits that underlie leech behavior. Studies that combine the unique features of the leech with modern optical and genetic techniques are also discussed. Thus, this Commentary aims to explain the continued appeal of the leech as an experimental animal in the 21st century.”,”DOI”:”10.1242/jeb.113860″,”ISSN”:”0022-0949, 1477-9145″,”note”:”PMID: 26538172″,”shortTitle”:”A classic model animal in the 21st century”,”language”:”en”,”author”:{“family”:”Wagenaar”,”given”:”Daniel A.”},”issued”:{“date-parts”:”2015″,11,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Wagenaar, 2015). According to Elliott and Kutschera (2011), Hirudo medicinalis, H. verbena and Hirudinaria manillensis are very much closely related. This phylogenetic relationship between them can be proven by using molecular methodology.

Figure 2.2: The dorsal and ventral side of A (Hirudinaria Javanica), B (Hirudinaria manillensis) and C (Hirudinaria sp.) ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”LywahKSu”,”properties”:{“formattedCitation”:”(Tubtimon et al., 2014)”,”plainCitation”:”(Tubtimon et al., 2014)”,”noteIndex”:0},”citationItems”:{“id”:171,”uris”:”http://zotero.org/users/local/izdntZkG/items/8UULDL9U”,”uri”:”http://zotero.org/users/local/izdntZkG/items/8UULDL9U”,”itemData”:{“id”:171,”type”:”article-journal”,”title”:”Systematics of the freshwater leech genus Hirudinaria Whitman, 1886 (Arhynchobdellida, Hirudinidae) from northeastern Thailand”,”container-title”:”ZooKeys”,”page”:”15-33″,”volume”:”452″,”source”:”zookeys.pensoft.net”,”abstract”:”In total, 435 specimens of the Southeast Asian freshwater leech species within the Hirudinidae family were collected from 17 locations of various types of aquatic habitats in northeastern Thailand. They were all morphologically placed within the genus Hirudinaria Whitman, 1886 and there were three distinct species: the common Hirudinaria manillensis, 78.2% of all collected specimens and at all 17 locations, Hirudinaria javanica at 20.3% of collected samples and from five locations and a rarer unidentified morphospecies (Hirudinaria sp.) with six samples from only two locations. The karyotypes of these three species were examined across their range in this study area for 38, 11 and 6 adult specimens of Hirudinaria manillensis, Hirudinaria javanica and Hirudinaria sp., respectively. This revealed different chromosome numbers among all three species, with Hirudinaria javanica having n = 13, 2n = 26, Hirudinaria manillensis lacked one small chromosome pair with n = 12, 2n = 24, and the unknown Hirudinaria sp. differed from any known Hirudinaria karyotypes in exhibiting a higher chromosome number (n = 14, 2n = 28) and a gradual change in size from large to small chromosomes. This suggests that the unknown Hirudinaria sp. is a new biological species. However, phylogenetic analysis based upon a 658 bp fragment of the cytochrome oxidase subunit I gene placed this unknown morphospecies within the Hirudinaria manillensis clade, perhaps then suggesting a recent sympatric speciation, although this requires further confirmation. Regardless, the chromosomes of all three species were asymmetric, most with telocentric elements. A distinct bi-armed chromosome marker was present on the first chromosome pair in Hirudinaria javanica, whilst it was on pairs 1, 2, 3 and 5 in Hirudinaria manillensis, and on pairs 3 and 5 for the unknown Hirudinaria sp.”,”DOI”:”10.3897/zookeys.452.7528″,”ISSN”:”1313-2970″,”language”:”en”,”author”:{“family”:”Tubtimon”,”given”:”Jaruwan”},{“family”:”Jeratthitikul”,”given”:”Ekgachai”},{“family”:”Sutcharit”,”given”:”Chirasak”},{“family”:”Kongim”,”given”:”Bangon”},{“family”:”Panha”,”given”:”Somsak”},”issued”:{“date-parts”:”2014″,4,11}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Tubtimon et al., 2014)
2.7.1.1 Leech central nervous system
Leech nervous system consists of a head ganglion, 21 body ganglia and 7 fused tail ganglia. Besides, the leech’s ganglia are joined with connective of the leech. Connective in leech nervous system consists of two big lateral bundles of nerve fibres and a thin medial connective which can be called as Faivre’s nerve. Next, the ganglion contains neurophil glia, endothelial wall, outer capsule, neurophil, neurons and packet glial cell. Moreover, leech’s microglia is proven to exhibit both neuroprotective and neurotoxic effects since it regulates the tissue homeostasis in the CNS ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”RfC7oOOH”,”properties”:{“formattedCitation”:”(Le Marrec-Croq et al., 2013)”,”plainCitation”:”(Le Marrec-Croq et al., 2013)”,”noteIndex”:0},”citationItems”:{“id”:184,”uris”:”http://zotero.org/users/local/izdntZkG/items/5KWAGJQT”,”uri”:”http://zotero.org/users/local/izdntZkG/items/5KWAGJQT”,”itemData”:{“id”:184,”type”:”webpage”,”title”:”The Leech Nervous System: A Valuable Model to Study the Microglia Involvement in Regenerative Processes”,”container-title”:”Journal of Immunology Research”,”genre”:”Research article”,”abstract”:”Microglia are intrinsic components of the central nervous system (CNS). During pathologies in mammals, inflammatory processes implicate the resident microglia and the infiltration of blood cells including macrophages. Functions of microglia appear to be complex as they exhibit both neuroprotective and neurotoxic effects during neuropathological conditions in vivo and in vitro. The medicinal leech Hirudo medicinalis is a well-known model in neurobiology due to its ability to naturally repair its CNS following injury. Considering the low infiltration of blood cells in this process, the leech CNS is studied to specify the activation mechanisms of only resident microglial cells. The microglia recruitment is known to be essential for the usual sprouting of injured axons and does not require any other glial cells. The present review will describe the questions which are addressed to understand the nerve repair. They will discuss the implication of leech factors in the microglial accumulation, the identification of nerve cells producing these molecules, and the study of different microglial subsets. Those questions aim to better understand the mechanisms of microglial cell recruitment and their crosstalk with damaged neurons. The study of this dialog is necessary to elucidate the balance of the inflammation leading to the leech CNS repair.”,”URL”:”https://www.hindawi.com/journals/jir/2013/274019/”,”note”:”PMID: 23878582
DOI: 10.1155/2013/274019″,”shortTitle”:”The Leech Nervous System”,”language”:”en”,”author”:{“family”:”Le Marrec-Croq”,”given”:”Françoise”},{“family”:”Drago”,”given”:”Francesco”},{“family”:”Vizioli”,”given”:”Jacopo”},{“family”:”Sautière”,”given”:”Pierre-Eric”},{“family”:”Lefebvre”,”given”:”Christophe”},”issued”:{“date-parts”:”2013″},”accessed”:{“date-parts”:”2018″,4,8}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Le Marrec-Croq et al., 2013).

Figure 2.3: (a) Diagram of leech nervous system containing ganglion and connectives, (b) The dorsal view of ganglion. ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”lWEvPZAe”,”properties”:{“formattedCitation”:”(Le Marrec-Croq et al., 2013)”,”plainCitation”:”(Le Marrec-Croq et al., 2013)”,”noteIndex”:0},”citationItems”:{“id”:184,”uris”:”http://zotero.org/users/local/izdntZkG/items/5KWAGJQT”,”uri”:”http://zotero.org/users/local/izdntZkG/items/5KWAGJQT”,”itemData”:{“id”:184,”type”:”webpage”,”title”:”The Leech Nervous System: A Valuable Model to Study the Microglia Involvement in Regenerative Processes”,”container-title”:”Journal of Immunology Research”,”genre”:”Research article”,”abstract”:”Microglia are intrinsic components of the central nervous system (CNS). During pathologies in mammals, inflammatory processes implicate the resident microglia and the infiltration of blood cells including macrophages. Functions of microglia appear to be complex as they exhibit both neuroprotective and neurotoxic effects during neuropathological conditions in vivo and in vitro. The medicinal leech Hirudo medicinalis is a well-known model in neurobiology due to its ability to naturally repair its CNS following injury. Considering the low infiltration of blood cells in this process, the leech CNS is studied to specify the activation mechanisms of only resident microglial cells. The microglia recruitment is known to be essential for the usual sprouting of injured axons and does not require any other glial cells. The present review will describe the questions which are addressed to understand the nerve repair. They will discuss the implication of leech factors in the microglial accumulation, the identification of nerve cells producing these molecules, and the study of different microglial subsets. Those questions aim to better understand the mechanisms of microglial cell recruitment and their crosstalk with damaged neurons. The study of this dialog is necessary to elucidate the balance of the inflammation leading to the leech CNS repair.”,”URL”:”https://www.hindawi.com/journals/jir/2013/274019/”,”note”:”PMID: 23878582
DOI: 10.1155/2013/274019″,”shortTitle”:”The Leech Nervous System”,”language”:”en”,”author”:{“family”:”Le Marrec-Croq”,”given”:”Françoise”},{“family”:”Drago”,”given”:”Francesco”},{“family”:”Vizioli”,”given”:”Jacopo”},{“family”:”Sautière”,”given”:”Pierre-Eric”},{“family”:”Lefebvre”,”given”:”Christophe”},”issued”:{“date-parts”:”2013″},”accessed”:{“date-parts”:”2018″,4,8}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Le Marrec-Croq et al., 2013)
Leech nervous system is very simple and also well studied by researchers around the world. There are 32 bilateral neuromeres in leech nervous system. Besides, the 4 anterior-most neuromeres are fuse to created sub-esophageal while 7-posterior neuromeres fuse to become the tail ganglion of the leech. Moreover, the head ganglion of the leech is formed by supra-esophageal ring of the non-segmental origin and sub esophageal ganglion together ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”wk6FfQIv”,”properties”:{“formattedCitation”:”(Salzet and Macagno, 2009)”,”plainCitation”:”(Salzet and Macagno, 2009)”,”noteIndex”:0},”citationItems”:{“id”:192,”uris”:”http://zotero.org/users/local/izdntZkG/items/VI22TW22″,”uri”:”http://zotero.org/users/local/izdntZkG/items/VI22TW22″,”itemData”:{“id”:192,”type”:”chapter”,”title”:”Development, Regeneration and Immune Responses of the Leech Nervous System”,”container-title”:”Annelids in Modern Biology”,”publisher”:”Wiley-Blackwell”,”page”:”156-184″,”source”:”onlinelibrary-wiley-com.ezaccess.library.uitm.edu.my”,”URL”:”https://onlinelibrary-wiley-com.ezaccess.library.uitm.edu.my/doi/abs/10.1002/9780470455203.ch9″,”ISBN”:”978-0-470-45520-3″,”note”:”DOI: 10.1002/9780470455203.ch9″,”language”:”en”,”author”:{“family”:”Salzet”,”given”:”Michel”},{“family”:”Macagno”,”given”:”Eduardo”},”issued”:{“date-parts”:”2009″,4,21},”accessed”:{“date-parts”:”2018″,4,8}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Salzet and Macagno, 2009).

2.7.2SH-SY5Y human neuroblastoma cell line
The human neuroblastoma cell line are broadly used as a model system for neural cellular ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”blo5rxqX”,”properties”:{“formattedCitation”:”(Gilany et al., 2008)”,”plainCitation”:”(Gilany et al., 2008)”,”noteIndex”:0},”citationItems”:{“id”:297,”uris”:”http://zotero.org/users/local/izdntZkG/items/QJKDR3F4″,”uri”:”http://zotero.org/users/local/izdntZkG/items/QJKDR3F4″,”itemData”:{“id”:297,”type”:”article-journal”,”title”:”The proteome of the human neuroblastoma cell line SH-SY5Y: An enlarged proteome”,”container-title”:”Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics”,”page”:”983-985″,”volume”:”1784″,”issue”:”7″,”source”:”ScienceDirect”,”abstract”:”The human neuroblastoma cell line SH-SY5Y (ATCC: CRL-2266) is widely used as a neural cellular model system. The hitherto existing proteome data (115 proteins) are here extended. A total of 1103 unique proteins of this cell line were identified using 2D-LC combined with MALDI-TOF/TOF-MS, SDS-PAGE with nano-LC–MS/MS, N-terminal COFRADIC analysis with nano-LC–MS/MS and 2D-PAGE with MALDI-TOF/TOF-MS peptide mass fingerprinting. The obtained proteome profile of this cell line is discussed.”,”DOI”:”10.1016/j.bbapap.2008.03.003″,”ISSN”:”1570-9639″,”shortTitle”:”The proteome of the human neuroblastoma cell line SH-SY5Y”,”journalAbbreviation”:”Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics”,”author”:{“family”:”Gilany”,”given”:”Kambiz”},{“family”:”Van Elzen”,”given”:”Roos”},{“family”:”Mous”,”given”:”Kim”},{“family”:”Coen”,”given”:”Edmond”},{“family”:”Van Dongen”,”given”:”Walter”},{“family”:”Vandamme”,”given”:”Stefaan”},{“family”:”Gevaert”,”given”:”Kris”},{“family”:”Timmerman”,”given”:”Evy”},{“family”:”Vandekerckhove”,”given”:”Joël”},{“family”:”Dewilde”,”given”:”Sylvia”},{“family”:”Van Ostade”,”given”:”Xaveer”},{“family”:”Moens”,”given”:”Luc”},”issued”:{“date-parts”:”2008″,7,1}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Gilany et al., 2008). SH-SY5Y is derived from the parental line SK-N-SH. It is a transformed neuronal-like cell line which originally comes from metastatic bone tumor biopsy. Moreover, parental line SK-N-SH consist of two morphological distinct phenotypes which are epithelial-like cells and neuroblast-like cells ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”GCmfA5xl”,”properties”:{“formattedCitation”:”(Kovalevich and Langford, 2013)”,”plainCitation”:”(Kovalevich and Langford, 2013)”,”noteIndex”:0},”citationItems”:{“id”:247,”uris”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”uri”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”itemData”:{“id”:247,”type”:”article-journal”,”title”:”Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology”,”container-title”:”Methods in molecular biology (Clifton, N.J.)”,”page”:”9-21″,”volume”:”1078″,”source”:”PubMed Central”,”abstract”:”The use of primary mammalian neurons derived from embryonic central nervous system tissue is limited by the fact that once terminally differentiated into mature neurons, the cells can no longer be propagated. Transformed neuronal-like cell lines can be used in vitro to overcome this limitation. However, several caveats exist when utilizing cells derived from malignant tumors. In this context, the popular SH-SY5Y neuroblastoma cell line and its use in in vitro systems is described. Originally derived from a metastatic bone tumor biopsy, SH-SY5Y (ATCC® CRL-2266™) cells are a subline of the parental line SK-N-SH (ATCC® HTB-11™). SK-N-SH were subcloned three times; first to SH-SY, then to SH-SY5, and finally to SH-SY5Y. SH-SY5Y were deposited to the ATCC® in 1970 by June L. Biedler., Three important characteristics of SH-SY5Y cells should be considered when using these cells in in vitro studies. First, cultures include both adherent and floating cells, both types of which are viable. Few studies address the biological significance of the adherent versus floating phenotypes, but most reported studies utilize adherent populations and discard the floating cells during media changes. Second, early studies by Biedler’s group indicated that the parental differentiated SK-N-SH cells contained two morphologically distinct phenotypes: neuroblast-like cells and epithelial-like cells (Ross et al., J Nat Cancer Inst 71:741–747, 1983). These two phenotypes may correspond to the “N” and “S” types described in later studies in SH-SY5Y by Encinas et al. (J Neurochem 75:991–1003, 2000). Cells with neuroblast-like morphology are positive for tyrosine hydroxylase (TH) and dopamine-?-hydroxylase characteristic of catecholaminergic neurons, whereas the epithelial-like counterpart cells lacked these enzymatic activities (Ross et al., J Nat Cancer Inst 71:741–747, 1983). Third, SH-SY5Y cells can be differentiated to a more mature neuron-like phenotype that is characterized by neuronal markers. There are several methods to differentiate SH-SY5Y cells and are mentioned below. Retinoic acid is the most commonly used means for differentiation and will be addressed in detail.”,”DOI”:”10.1007/978-1-62703-640-5_2″,”ISSN”:”1064-3745″,”note”:”PMID: 23975817
PMCID: PMC5127451″,”journalAbbreviation”:”Methods Mol Biol”,”author”:{“family”:”Kovalevich”,”given”:”Jane”},{“family”:”Langford”,”given”:”Dianne”},”issued”:{“date-parts”:”2013″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kovalevich and Langford, 2013). The neuroblast-like cell is when the SH-SY5Y cells is in the undifferentiated form. The structure of undifferentiated cell is in clusters and clumps. This is because the cell grows on top of each other as it is continuously proliferate. They are also lack of the neuronal marker ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”8Dn8S40z”,”properties”:{“formattedCitation”:”(P\uc0\u229{}hlman et al., 1984)”,”plainCitation”:”(Påhlman et al., 1984)”,”noteIndex”:0},”citationItems”:{“id”:302,”uris”:”http://zotero.org/users/local/izdntZkG/items/BPDJQD5X”,”uri”:”http://zotero.org/users/local/izdntZkG/items/BPDJQD5X”,”itemData”:{“id”:302,”type”:”article-journal”,”title”:”Retinoic acid-induced differentiation of cultured human neuroblastoma cells: a comparison with phorbolester-induced differentiation”,”container-title”:”Cell Differentiation”,”page”:”135-144″,”volume”:”14″,”issue”:”2″,”source”:”PubMed”,”abstract”:”Cultured human SH-SY5Y neuroblastoma cells differentiated in the presence of retinoic acid (RA) or 12-0-tetradecanoyl-phorbol-13-acetate (TPA). In both cases, the cells acquired long cell processes and the cell growth was partially inhibited. Treatment with RA or TPA resulted in an increased neuron-specific enolase activity, relative to the total cellular enolase activity. At the optimal concentration, TPA induced a 200-fold increase in the concentration of noradrenalin, whereas in RA-treated cells the corresponding increase was only fourfold. Cells treated with a combination of RA and TPA were morphologically differentiated and growth inhibited and had a high relative activity of neuron-specific enolase. The increase in the concentration of noradrenalin induced by TPA was inhibited by RA in a concentration-dependent fashion. However, despite this result there seemed to be no general antagonistic effect of RA on the TPA-induced differentiation. The phenotypes of the cells treated by RA, TPA, or the combination of RA and TPA, did, on the other hand, differ from each other. Our results suggest that RA and TPA induce the SH-SY5Y cells to differentiate along different pathways.”,”ISSN”:”0045-6039″,”note”:”PMID: 6467378″,”shortTitle”:”Retinoic acid-induced differentiation of cultured human neuroblastoma cells”,”journalAbbreviation”:”Cell Differ.”,”language”:”eng”,”author”:{“family”:”Påhlman”,”given”:”S.”},{“family”:”Ruusala”,”given”:”A. I.”},{“family”:”Abrahamsson”,”given”:”L.”},{“family”:”Mattsson”,”given”:”M. E.”},{“family”:”Esscher”,”given”:”T.”},”issued”:{“date-parts”:”1984″,6}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Påhlman et al., 1984).

Figure 2.4: Undifferentiated of SH-SY5Y cells ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”pfl48pRM”,”properties”:{“formattedCitation”:”(Kovalevich and Langford, 2013)”,”plainCitation”:”(Kovalevich and Langford, 2013)”,”noteIndex”:0},”citationItems”:{“id”:247,”uris”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”uri”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”itemData”:{“id”:247,”type”:”article-journal”,”title”:”Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology”,”container-title”:”Methods in molecular biology (Clifton, N.J.)”,”page”:”9-21″,”volume”:”1078″,”source”:”PubMed Central”,”abstract”:”The use of primary mammalian neurons derived from embryonic central nervous system tissue is limited by the fact that once terminally differentiated into mature neurons, the cells can no longer be propagated. Transformed neuronal-like cell lines can be used in vitro to overcome this limitation. However, several caveats exist when utilizing cells derived from malignant tumors. In this context, the popular SH-SY5Y neuroblastoma cell line and its use in in vitro systems is described. Originally derived from a metastatic bone tumor biopsy, SH-SY5Y (ATCC® CRL-2266™) cells are a subline of the parental line SK-N-SH (ATCC® HTB-11™). SK-N-SH were subcloned three times; first to SH-SY, then to SH-SY5, and finally to SH-SY5Y. SH-SY5Y were deposited to the ATCC® in 1970 by June L. Biedler., Three important characteristics of SH-SY5Y cells should be considered when using these cells in in vitro studies. First, cultures include both adherent and floating cells, both types of which are viable. Few studies address the biological significance of the adherent versus floating phenotypes, but most reported studies utilize adherent populations and discard the floating cells during media changes. Second, early studies by Biedler’s group indicated that the parental differentiated SK-N-SH cells contained two morphologically distinct phenotypes: neuroblast-like cells and epithelial-like cells (Ross et al., J Nat Cancer Inst 71:741–747, 1983). These two phenotypes may correspond to the “N” and “S” types described in later studies in SH-SY5Y by Encinas et al. (J Neurochem 75:991–1003, 2000). Cells with neuroblast-like morphology are positive for tyrosine hydroxylase (TH) and dopamine-?-hydroxylase characteristic of catecholaminergic neurons, whereas the epithelial-like counterpart cells lacked these enzymatic activities (Ross et al., J Nat Cancer Inst 71:741–747, 1983). Third, SH-SY5Y cells can be differentiated to a more mature neuron-like phenotype that is characterized by neuronal markers. There are several methods to differentiate SH-SY5Y cells and are mentioned below. Retinoic acid is the most commonly used means for differentiation and will be addressed in detail.”,”DOI”:”10.1007/978-1-62703-640-5_2″,”ISSN”:”1064-3745″,”note”:”PMID: 23975817
PMCID: PMC5127451″,”journalAbbreviation”:”Methods Mol Biol”,”author”:{“family”:”Kovalevich”,”given”:”Jane”},{“family”:”Langford”,”given”:”Dianne”},”issued”:{“date-parts”:”2013″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kovalevich and Langford, 2013)
Meanwhile, a differentiated SH-SY5Y cell contains pyramidal shaped and not cluster form like in undifferentiated SH-SY5Y. This is because of low proliferation of cells. Retinoic Acid is responsible for differentiation as it is a vitamin A derivative ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”aYzuG6q4″,”properties”:{“formattedCitation”:”(Kovalevich and Langford, 2013)”,”plainCitation”:”(Kovalevich and Langford, 2013)”,”noteIndex”:0},”citationItems”:{“id”:247,”uris”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”uri”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”itemData”:{“id”:247,”type”:”article-journal”,”title”:”Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology”,”container-title”:”Methods in molecular biology (Clifton, N.J.)”,”page”:”9-21″,”volume”:”1078″,”source”:”PubMed Central”,”abstract”:”The use of primary mammalian neurons derived from embryonic central nervous system tissue is limited by the fact that once terminally differentiated into mature neurons, the cells can no longer be propagated. Transformed neuronal-like cell lines can be used in vitro to overcome this limitation. However, several caveats exist when utilizing cells derived from malignant tumors. In this context, the popular SH-SY5Y neuroblastoma cell line and its use in in vitro systems is described. Originally derived from a metastatic bone tumor biopsy, SH-SY5Y (ATCC® CRL-2266™) cells are a subline of the parental line SK-N-SH (ATCC® HTB-11™). SK-N-SH were subcloned three times; first to SH-SY, then to SH-SY5, and finally to SH-SY5Y. SH-SY5Y were deposited to the ATCC® in 1970 by June L. Biedler., Three important characteristics of SH-SY5Y cells should be considered when using these cells in in vitro studies. First, cultures include both adherent and floating cells, both types of which are viable. Few studies address the biological significance of the adherent versus floating phenotypes, but most reported studies utilize adherent populations and discard the floating cells during media changes. Second, early studies by Biedler’s group indicated that the parental differentiated SK-N-SH cells contained two morphologically distinct phenotypes: neuroblast-like cells and epithelial-like cells (Ross et al., J Nat Cancer Inst 71:741–747, 1983). These two phenotypes may correspond to the “N” and “S” types described in later studies in SH-SY5Y by Encinas et al. (J Neurochem 75:991–1003, 2000). Cells with neuroblast-like morphology are positive for tyrosine hydroxylase (TH) and dopamine-?-hydroxylase characteristic of catecholaminergic neurons, whereas the epithelial-like counterpart cells lacked these enzymatic activities (Ross et al., J Nat Cancer Inst 71:741–747, 1983). Third, SH-SY5Y cells can be differentiated to a more mature neuron-like phenotype that is characterized by neuronal markers. There are several methods to differentiate SH-SY5Y cells and are mentioned below. Retinoic acid is the most commonly used means for differentiation and will be addressed in detail.”,”DOI”:”10.1007/978-1-62703-640-5_2″,”ISSN”:”1064-3745″,”note”:”PMID: 23975817
PMCID: PMC5127451″,”journalAbbreviation”:”Methods Mol Biol”,”author”:{“family”:”Kovalevich”,”given”:”Jane”},{“family”:”Langford”,”given”:”Dianne”},”issued”:{“date-parts”:”2013″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kovalevich and Langford, 2013).

Figure 2.5: Differentiated of SH-SY5Y cells ADDIN ZOTERO_ITEM CSL_CITATION {“citationID”:”qtTjiiaJ”,”properties”:{“formattedCitation”:”(Kovalevich and Langford, 2013)”,”plainCitation”:”(Kovalevich and Langford, 2013)”,”noteIndex”:0},”citationItems”:{“id”:247,”uris”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”uri”:”http://zotero.org/users/local/izdntZkG/items/732GU5XA”,”itemData”:{“id”:247,”type”:”article-journal”,”title”:”Considerations for the Use of SH-SY5Y Neuroblastoma Cells in Neurobiology”,”container-title”:”Methods in molecular biology (Clifton, N.J.)”,”page”:”9-21″,”volume”:”1078″,”source”:”PubMed Central”,”abstract”:”The use of primary mammalian neurons derived from embryonic central nervous system tissue is limited by the fact that once terminally differentiated into mature neurons, the cells can no longer be propagated. Transformed neuronal-like cell lines can be used in vitro to overcome this limitation. However, several caveats exist when utilizing cells derived from malignant tumors. In this context, the popular SH-SY5Y neuroblastoma cell line and its use in in vitro systems is described. Originally derived from a metastatic bone tumor biopsy, SH-SY5Y (ATCC® CRL-2266™) cells are a subline of the parental line SK-N-SH (ATCC® HTB-11™). SK-N-SH were subcloned three times; first to SH-SY, then to SH-SY5, and finally to SH-SY5Y. SH-SY5Y were deposited to the ATCC® in 1970 by June L. Biedler., Three important characteristics of SH-SY5Y cells should be considered when using these cells in in vitro studies. First, cultures include both adherent and floating cells, both types of which are viable. Few studies address the biological significance of the adherent versus floating phenotypes, but most reported studies utilize adherent populations and discard the floating cells during media changes. Second, early studies by Biedler’s group indicated that the parental differentiated SK-N-SH cells contained two morphologically distinct phenotypes: neuroblast-like cells and epithelial-like cells (Ross et al., J Nat Cancer Inst 71:741–747, 1983). These two phenotypes may correspond to the “N” and “S” types described in later studies in SH-SY5Y by Encinas et al. (J Neurochem 75:991–1003, 2000). Cells with neuroblast-like morphology are positive for tyrosine hydroxylase (TH) and dopamine-?-hydroxylase characteristic of catecholaminergic neurons, whereas the epithelial-like counterpart cells lacked these enzymatic activities (Ross et al., J Nat Cancer Inst 71:741–747, 1983). Third, SH-SY5Y cells can be differentiated to a more mature neuron-like phenotype that is characterized by neuronal markers. There are several methods to differentiate SH-SY5Y cells and are mentioned below. Retinoic acid is the most commonly used means for differentiation and will be addressed in detail.”,”DOI”:”10.1007/978-1-62703-640-5_2″,”ISSN”:”1064-3745″,”note”:”PMID: 23975817
PMCID: PMC5127451″,”journalAbbreviation”:”Methods Mol Biol”,”author”:{“family”:”Kovalevich”,”given”:”Jane”},{“family”:”Langford”,”given”:”Dianne”},”issued”:{“date-parts”:”2013″}}},”schema”:”https://github.com/citation-style-language/schema/raw/master/csl-citation.json”} (Kovalevich and Langford, 2013)
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