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      Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal

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          Abstract

          Neurodegenerative disorders which affects a larger population pose a great clinical challenge. These disorders impact the quality of life of an individual by damaging the neurons, which are the unit cells of the brain. Clinicians are faced with the grave challenge of inhibiting the progression of these diseases as available treatment options fail to meet the clinical demand. Thus, treating the disease/disorder symptomatically is the Hobson's choice. The goal of the researchers is to introduce newer therapies in this segment and introducing a new molecule will take long years of development. Hence, drug repurposing/repositioning can be a better substitute in comparison to time consuming and expensive drug discovery and development cycle. Presently, a paradigm shift towards the re-purposing of drugs can be witnessed. Statins which have been previously approved as anti-hyperlipidemic agents are in the limelight of research for re-purposed drugs. Owing to their anti-inflammatory and antioxidant nature, statins act as neuroprotective in several brain disorders. Further they attenuate the amyloid plaques and protein aggregation which are the triggering factors in the Alzheimer's and Parkinson's respectively. In case of Huntington disease and Multiple sclerosis they help in improving the psychomotor symptoms and stimulate remyelination thus acting as neuroprotective. This article reviews the potential of statins in treating neurodegenerative disorders along with a brief discussion on the safety concerns associated with use of statins and human clinical trial data linked with re-tasking statins for neurodegenerative disorders along with the regulatory perspectives involved with the drug repositioning.

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          Highlights

          • Neurodegenerative disease is one of the most prevailing disease sector.

          • Available therapy options provide only symptomatic relief and are incompetent.

          • The pleotropic actions of statins are efficient in treating neurodegenerative diseases.

          • Repurposing of drug offers a cheap, safer and quicker option to De-novo synthesis.

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          Most cited references75

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          Immunopathology of multiple sclerosis.

          Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.
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            Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease.

            Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain, which is characterized by the formation of extracellular amyloid plaques (or senile plaques) and intracellular neurofibrillary tangles. However, increasing evidences demonstrated that neuroinflammatory changes, including chronic microgliosis are key pathological components of AD. Microglia, the resident immune cells of the brain, is constantly survey the microenvironment under physiological conditions. In AD, deposition of β-amyliod (Aβ) peptide initiates a spectrum of cerebral neuroinflammation mediated by activating microglia. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Emerging studies have demonstrated that up-regulation of pro-inflammatory cytokines play multiple roles in both neurodegeneration and neuroprotection. Understanding the pro-inflammatory cytokines signaling pathways involved in the regulation of AD is crucial to the development of strategies for therapy. This review will discuss the mechanisms and important role of pro-inflammatory cytokines in the pathogenesis of AD, and the ongoing drug targeting pro-inflammatory cytokine for therapeutic modulation.
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              Parkinson disease: from pathology to molecular disease mechanisms.

              Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Curr Res Pharmacol Drug Discov
                Curr Res Pharmacol Drug Discov
                Current Research in Pharmacology and Drug Discovery
                Elsevier
                2590-2571
                31 December 2020
                2021
                31 December 2020
                : 2
                : 100012
                Affiliations
                [a ]Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
                [b ]Department of Pharmacology and Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
                Author notes
                []Corresponding author. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India. saurabh@ 123456niperhyd.ac.in
                [1]

                Aditi Bhat and Harshita Dalvi have contributed equally to this review article.

                Article
                S2590-2571(20)30014-6 100012
                10.1016/j.crphar.2020.100012
                8663947
                34909647
                784b22ad-6e42-4df5-99cf-3707d66ec571
                © 2020 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 1 October 2020
                : 15 December 2020
                : 18 December 2020
                Categories
                Review Article

                neurodegenerative disorders,statins,alzheimer disease,parkinson disease,huntington disease,multiple sclerosis

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