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      Anti-neuroinflammatory Potential of Natural Products in Attenuation of Alzheimer's Disease

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          Abstract

          Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder associated with dementia and cognitive impairment most common in elderly population. Various pathophysiological mechanisms have been proposed by numerous researcher, although, exact mechanism is not yet elucidated. Several studies have been indicated that neuroinflammation associated with deposition of amyloid- beta (Aβ) in brain is a major hallmark toward the pathology of neurodegenerative diseases. So, there is a need to unravel the link of inflammatory process in neurodegeneration. Increased microglial activation, expression of cytokines, reactive oxygen species (ROS), and nuclear factor kappa B (NF-κB) participate in inflammatory process of AD. This review mainly concentrates on involvement of neuroinflammation and the molecular mechanisms adapted by various natural compounds, phytochemicals and herbal formulations in various signaling pathways involved in neuroprotection. Currently, pharmacologically active natural products, having anti-neuroinflammatory potential are being focused which makes them potential candidate to cure AD. A number of preclinical and clinical trials have been done on nutritional and botanical agents. Analysis of anti-inflammatory and neuroprotective phytochemicals such as terpenoids, phenolic derivatives, alkaloids, glycosides, and steroidal saponins displays therapeutic potential toward amelioration and prevention of devastating neurodegeneration observed in AD.

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          A review on Alzheimer's disease pathophysiology and its management: an update.

          Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing.
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            Microglia and neuroinflammation: a pathological perspective

            Microglia make up the innate immune system of the central nervous system and are key cellular mediators of neuroinflammatory processes. Their role in central nervous system diseases, including infections, is discussed in terms of a participation in both acute and chronic neuroinflammatory responses. Specific reference is made also to their involvement in Alzheimer's disease where microglial cell activation is thought to be critically important in the neurodegenerative process.
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              Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice.

              Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-alpha. These cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumor necrosis factor alpha-converting enzyme, a primary candidate alpha-secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                29 May 2018
                2018
                : 9
                : 548
                Affiliations
                [1] 1Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University , Islamabad, Pakistan
                [2] 2Department of Neurosurgery, Rizhao Hospital of Traditional Chinese Medicine , Rizhao, China
                [3] 3College of Pharmacy, Seoul National University , Seoul, South Korea
                Author notes

                Edited by: Abdul Sadiq, University of Malakand, Pakistan

                Reviewed by: Umer Rashid, COMSATS Institute of Information Technology Abbottabad, Pakistan; Tie-Jun Li, Second Military Medical University, China; Muhammad Ikram, Pusan National University, South Korea

                *Correspondence: Salman Khan skhan@ 123456qau.edu.pk

                This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

                †These authors have contributed equally to this work.

                Article
                10.3389/fphar.2018.00548
                5986949
                29896105
                5cd81826-19d0-4e45-9300-9426f14785ca
                Copyright © 2018 Shal, Ding, Ali, Kim and Khan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 March 2018
                : 08 May 2018
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 151, Pages: 17, Words: 13105
                Funding
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: 2009-0083533
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                alzheimer's disease,neuroinflammation,natural products,herbal formulation,phytochemicals,neuroprotection

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