The dualistic role of the purinergic P2Y12-receptor in an in vivo model of Parkinson's disease: signalling pathway and novel therapeutic targets

Background: Ionizing radiation from telluric sources is unceasingly an unprotected pitfall to humans. Thus, the foremost contributors to human exposure are global and medical radiations. Various pieces of evidences assembled during preceding years reveal the pertinent role of ionizing radiation-induced oxidative stress in the progression of neurodegenerative insults such as Parkinson’s disease, which have been contributing to increased proliferation and generation of reactive oxygen species. Objective: This review delineates the role of ionizing radiation-induced oxidative stress in Parkinson’s disease and proposes novel therapeutic interventions of flavonoid family offering effective management and slowing down the progression of Parkinson’s disease. Method: Published papers were searched via MEDLINE, PubMed, etc. published to date for in-depth database collection. Results: The potential of oxidative damage may harm the non-targeted cells. It can also modulate the functions of central nervous system, such as protein misfolding, mitochondria dysfunction, increased levels of oxidized lipids, and dopaminergic cell death, which accelerates the progression of Parkinson’s disease at the molecular, cellular, or tissue levels. In Parkinson’s disease, reactive oxygen species exacerbate the production of nitric oxides and superoxides by activated microglia, rendering death of dopaminergic neuronal cell through different mechanisms. Conclusion: Rising interest has extensively engrossed on the clinical trial designs based on the plant derived family of antioxidants. They are known to exert multifarious impact either way in neuroprotection via directly suppressing ionizing radiation-induced oxidative stress and reactive oxygen species production or indirectly increasing the dopamine levels and activating the glial cells.

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The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson’s disease: a review of in vivo models

Reviews in the Neurosciences ◽

10.1515/revneuro-2012-0071 ◽

2013 ◽

Vol 24 (2) ◽

Cited By ~ 54

Author(s):

Hiroyasu Sato ◽

Takeo Kato ◽

Shigeki Arawaka

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

In Vivo Models

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Molecular Interactions of α-Synuclein, Mitochondria, and Cellular Degradation Pathways in Parkinson's Disease

Quality Control of Cellular Protein in Neurodegenerative Disorders - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-1317-0.ch008 ◽

2020 ◽

pp. 212-234

Author(s):

Mansi Verma ◽

Sujata Basu ◽

Manisha Singh ◽

Rachana R. ◽

Simrat Kaur ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Interactions ◽

Therapeutic Target ◽

Molecular Mechanisms ◽

Degradation Pathways ◽

Functional Changes ◽

The World ◽

Novel Therapeutic

Parkinson's disease (PD) has been reported to be the most common neurodegenerative diseases all over the world. Several proteins are associated and responsible for causing PD. One such protein is α-synuclein. This chapter discusses the role of α-synuclein in PD. Various genetic and epigenetic factors, which cause structural and functional changes for α-synuclein, have been described. Several molecular mechanisms, which are involved in regulating mitochondrial and lysosomal related pathways and are linked to α-synuclein, have been discussed in detail. The knowledge gathered is further discussed in terms of using α-synuclein as a diagnostic marker for PD and as a novel therapeutic target for the same.

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PL.02.01 Novel therapeutic targets for neuroprotection and disease modification in Parkinson's disease

European Neuropsychopharmacology ◽

10.1016/s0924-977x(13)70117-2 ◽

2013 ◽

Vol 23 ◽

pp. S107

Author(s):

A. Björklund

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Therapeutic Targets ◽

Disease Modification ◽

Novel Therapeutic

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Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice

10.1101/2020.12.07.414359 ◽

2020 ◽

Author(s):

Francois Singh ◽

Alan R. Prescott ◽

Graeme Ball ◽

Alastair D. Reith ◽

Ian G. Ganley

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Neurodegenerative Disorder ◽

Reporter Mice ◽

Lrrk2 G2019s ◽

Lrrk2 Kinase

AbstractParkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy. Here we investigated the role of LRRK2, a protein kinase frequently mutated in PD, on this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson’s disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.

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LincRNA-p21 Inhibits Cell Viability and Promotes Cell Apoptosis in Parkinson’s Disease through Activating α-Synuclein Expression

BioMed Research International ◽

10.1155/2018/8181374 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

Xiaonan Xu ◽

Chengle Zhuang ◽

Zimu Wu ◽

Hongyan Qiu ◽

Haixia Feng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Apoptosis ◽

Noncoding Rna ◽

Long Intergenic Noncoding Rna ◽

Novel Target ◽

Underlying Mechanisms

Long intergenic noncoding RNA-p21 (lincRNA-p21) has been reported to be increased in Parkinson’s disease (PD). However, the function and underlying mechanisms of lincRNA-p21 remain not clear. In order to explore the role of lincRNA-p21 in PD, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce in vivo PD model (C57BL/6 mice) and utilized N-methyl-4-phenylpyridinium (MPP+) to create in vitro PD model (SH-SY5Y cells). Results showed that the expression level of lincRNA-p21 was increased significantly in PD models. High abundance of lincRNA-p21 inhibited viability and promoted apoptosis markedly in SH-SY5Y cells treated with MPP+. Mechanistically, further experiments demonstrated that upregulation of lincRNA-p21 could sponge miR-1277-5p and indirectly increase the expression of α-synuclein to suppress viability and activate apoptosis in SH-SY5Y cells. In short, our study illustrated that lincRNA-p21/miR-1277-5p axis regulated viability and apoptosis in SH-SY5Y cells treated with MPP+ via targeting α-synuclein. LincRNA-p21 might be a novel target for PD.

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The Deficiency of Maged1 Attenuates Parkinson's Disease Progression by Inhibiting Apoptosis and Enhancing Autophagy in Mice

10.21203/rs.3.rs-92068/v1 ◽

2020 ◽

Author(s):

Jie Wang ◽

Wei-Yan You ◽

Qing Ye ◽

Jia-Qi Zhang ◽

Chuan He ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Signaling Pathway ◽

Knockout Mice ◽

Gene Transfection ◽

Motor Deficits ◽

Mice Model

Abstract Background: Melanoma-associated antigen D1 (Maged1) is expressed in most adult tissues, predominantly in the brain, and has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, circadian rhythm, and drug addiction. However, the role of Maged1 in Parkinson’s disease (PD) remains unclear.Methods: Immunostaining was performed to investigate the expression of Maged1 in the samples from mice and human. To make the acute mice model of PD, C57BL/6 mice and Maged1 knockout mice were injected with 20 mg/kg 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) four times, every 2-hour intervals. SY5Y cells were treated by 200 μM 1-Methyl-4-phenylpyridinium iodide (MPP+). To examine motor balance and coordination, the rotarod test and pole test were used. Then we further investigated the role of Maged1 deficiency in DA neurons by high-performance liquid chromatography, immunohistochemistry, western blot, CCK8 assay, and gene transfection in vivo or in vitro.Results: Maged1 was expressed in DA neurons of samples from mice and human. And the expression of Maged1 was time-dependently upregulated by the treatment with MPTP or MPP+ in vivo or in vitro. Knockout of Maged1 in mice partly rescued the motor deficits and the reduced levels of striatal dopamine and its metabolites by MPTP treatment. Moreover, Maged1 deficiency protected primary DA neurons and differentiated ReNcell VM cells from MPP+ toxicity. Furthermore, along with the overexpression or downregulation of Maged1 in cultured SH-SY5Y cells, the reduced the cell viability by MPP+ treatment was relatively aggerated or attenuated. The effect of Maged1 deficiency may be attributed to the upregulated Akt signaling pathway and the downregulated mTOR signaling pathway, which further attenuated the MPTP or MPP+ -induced cell apoptosis and impairment of autophagy. Consistent with the above data, the degeneration of midbrain and striatum among 15-m Maged1 knockout mice was relatively mild compared to those in 15-m wild-type mice under physiological conditions.Conclusions: Maged1 deficiency-mediated apoptosis inhibition and autophagy enhancement may be a potential pro-survival mechanism during the progression of PD.

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In silico docking of Novel Phytoalkaloid Camalexin in the Management of Benomyl Induced Parkinson's disease and its In vivo Evaluation by Zebrafish Model

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210903091447 ◽

2021 ◽

Vol 20 ◽

Author(s):

Tamilanban T ◽

Manasa K ◽

Chitra V

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Aldehyde Dehydrogenase ◽

Neuronal Degeneration ◽

In Vivo Model ◽

Zebrafish Model ◽

Standard Drug ◽

In Silico Docking ◽

Dehydrogenase Enzyme

Background: Parkinson’s disease (PD) exhibits the extra pyramidal symptoms caused due to the dopaminergic neuronal degeneration in the substantia nigra of the brain and depletion of aldehyde dehydrogenase (ALDH) enzyme. Objective: This study was designed to enlighten the importance of Aldehyde dehydrogenase enzyme in protecting the dopamine levels in a living system. Camalexin, a potentially active compound has been evaluated for its dopamine enhancing and aldehyde dehydrogenase protecting role in pesticide induced Parkinson’s disease. Methods: AutoDock 4.2 software was employed to perform the docking simulations between the ligand camalexin and standard drugs Alda-1, Ropirinole with three proteins 4WJR, 3INL, 5AER. Consequently, the compound was evaluated for its in vivo neuroprotective role in zebrafish model by attaining Institutional Animal Ethical Committee permission. The behavioral assessments and catecholamine analysis in zebrafish were performed. Results: The Autodock result shows that the ligand camalexin has a lower binding energy (-3.84) that indicate higher affinity with the proteins when compared to the standard drug of proteins (-3.42). In zebrafish model, behavioral studies provided an evidence that camalexin helps in improvement of motor functions and cognition. The catecholamine assay has proved there is an enhancement in dopamine levels, as well as an improvement in aldehyde dehydrogenase enzyme also. Conclusion: The novel compound, camalexin, hence offers a protective role in Parkinson’s disease model by its interaction with neurochemical proteins and also in alternative in vivo model.

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