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      Targeting Sigma-1 Receptor: A Promising Strategy in the Treatment of Parkinson’s Disease

      review-article
      Author(s): ,
      Publication date (Electronic):
      Journal: Neurochemical Research
      Publisher: Springer US
      Keywords: Parkinson’s disease, Sigma-1 receptor, S1R agonists, Neuroprotection

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          Abstract

          Parkinson’s disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta region. Parkinson’s disease patients exhibit motor symptoms like tremors, rigidity, bradykinesia/hypokinesia, and non-motor symptoms like depression, cognitive decline, delusion, and pain. Major pathophysiological factors which contribute to neuron loss include excess/misfolded alpha-synuclein aggregates, microglial cell-mediated neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function. Sigma-1 receptors are molecular chaperones located at mitochondria-associated ER membrane. Their activation (by endogenous ligands or agonists) has shown neuroprotective and neurorestorative effects in various diseases. This review discusses the roles of activated Sig-1 receptors in modulating various pathophysiological features of Parkinson’s disease like alpha-synuclein aggregates, neuroinflammation, excitotoxicity, and oxidative stress.

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          ER stress-induced cell death mechanisms.

          Renata Sano, John C. Reed (2013)
          The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways. © 2013.
          Article 0 comments Cited 759 times – based on 0 reviews     Review now
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            Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases.

            De-Yu Tang, Weidong Le (2016)
            One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease (AD), and amyotrophic lateral sclerosis, is microglia-mediated neuroinflammation. Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M1 phenotype and M2 phenotype. Depending on the phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects. In this review, we focus on the potential role of M1 and M2 microglia and the dynamic changes of M1/M2 phenotypes that are critically associated with the neurodegenerative diseases. Generally, M1 microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair process of M2 microglia are dampened. This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed β-amyloid (Aβ) plaque and tangles that are released into the extracellular space. The endogenous stimuli including aggregated α-synuclein, mutated superoxide dismutase, Aβ, and tau oligomers exist in the milieu that may persistently activate M1 pro-inflammatory responses and finally lead to irreversible neuron loss. The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.
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              ERK/MAPK signalling pathway and tumorigenesis

              Yan-Jun Guo, Wei-Wei Pan, Sheng-Bing Liu … (2020)
              Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.
              Article 0 comments Cited 578 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Lokesh Kumar Bhatt:
                ORCID: http://orcid.org/0000-0002-4302-9300
                bhatt.lokesh@gmail.com
                Journal
                Journal ID (nlm-ta): Neurochem Res
                Journal ID (iso-abbrev): Neurochem Res
                Title: Neurochemical Research
                Publisher: Springer US (New York )
                ISSN (Print): 0364-3190
                ISSN (Electronic): 1573-6903
                Publication date (Electronic): 31 May 2023
                Pages: 1-11
                Affiliations
                GRID grid.430221.6, ISNI 0000 0004 1755 6697, Department of Pharmacology, , SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, ; Vile Parle (West), Mumbai, 400056 India
                Author information
                http://orcid.org/0000-0002-4302-9300
                Article
                Publisher ID: 3960
                DOI: 10.1007/s11064-023-03960-6
                PMC ID: 10231286
                PubMed ID: 37259012
                SO-VID: 6ae2e860-220d-4b8f-aab8-8f14d511b79e
                Copyright © © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 1 March 2023
                Date revision received : 16 May 2023
                Date accepted : 23 May 2023
                Categories
                Subject: Review

                ScienceOpen disciplines: Neurosciences
                Keywords: parkinson’s disease,sigma-1 receptor,s1r agonists,neuroprotection
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: parkinson’s disease, sigma-1 receptor, s1r agonists, neuroprotection

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