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Central Nervous System Agents in Medicinal Chemistry


ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Review Article

Novel Molecular Targets and Mechanisms for Neuroprotective Modulation in Neurodegenerative Disorders

Author(s): Aala Azari, Amin Goodarzi, Behrouz Jafarkhani, Mohammad Eghbali, Zohreh Karimi, Seyed Sajad Hosseini Balef and Hamid Irannejad*

Volume 22, Issue 2, 2022

Published on: 22 July, 2022

Page: [88 - 107] Pages: 20

DOI: 10.2174/1871524922666220616092132

Price: $65


Background: Neuronal death underlies the symptoms of several human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis and their precise pathophysiology have not yet been elucidated. According to various studies, the prohibition is the best therapy with neuroprotective approaches, which are advanced and safe methods.

Methods: This review summarizes some of the already-known and newly emerged neuroprotective targets and strategies and their experimental effects have also been reported. Accordingly, literature was studied from 2000 to 2021, and appropriate articles were searched in Google Scholar and Scopus with the keywords given in the keywords section of the current review.

Results: Lewy bodies are the histopathologic characteristics of neurodegenerative disorders and are protein-rich intracellular deposits in which Alpha-synuclein is its major protein. Alphasynuclein’s toxic potential provides a compelling rationale for therapeutic strategies aimed at decreasing its burden in neuronal cells through numerous pathways, including ubiquitin-proteasome system and autophagy-lysosome pathway, proteolytic breakdown via cathepsin D, kallikrein-6 (neurosin), calpain-1 or MMP9, heat shock proteins, and proteolysis targeting chimera which consists of a target protein-ligand and an E3 ubiquitin ligase (E3) followed by target protein ubiquitination (PROTACs). Other targets that have been noticed recently are the mutant huntingtin, tau proteins and glycogen synthase kinase 3β; their accumulation proceeds extensive neuronal damage and up to the minute approach such as proteolysis targeting chimera promotes its degradation in cells. Various studies demonstrated that Mendelian gene mutations can result in neurodegenerative diseases. An additional target that has gained much interest is epigenetics, such as mutation, phosphodiesterase, RNA binding proteins and Nuclear respiratory factor 1.

Conclusion: The novel molecular targets and new strategies compiled and introduced here can be used by scientists to design and discover more efficient small molecule drugs against neurodegenerative diseases. And also, the genes in which their mutations can lead to the α-synuclein aggregation or accumulation have been discussed and considered a valuable information on epigenetics in dementia.

Keywords: Neuroprotection, α-synuclein, ubiquitin-proteasome system, PROTAC, heat shock protein, autophagy, epigenetics.

Graphical Abstract
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