Swertiamarin from Enicostemma littorale, counteracts PD associated neurotoxicity via enhancement α-synuclein suppressive genes and SKN-1/NRF-2 activation through MAPK pathway

Pandey, Taruna; Shukla, Aparna; Trivedi, Mashu; Khan, Feroz; Pandey, Rakesh

doi:10.1016/j.bioorg.2021.104655

Cited by 12 publications

(9 citation statements)

References 48 publications

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“…We have selected SWE, a wellreported molecule, for its potent anti-inflammatory activities, and its beneficial effects have been exhibited in the C. elegans model of PD. 23 Here, we report the results of in vitro studies, where the effect of SWE on LPS-induced C6 glial cell activation was tested. Further, the compound was administered to a rotenone mouse PD model to understand and evaluate the potential of SWE.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…20−22 Recently, SWE demonstrated its neuroprotective effect in the α-syn-overexpressing transgenic and 6-hydroxydopamine (6-OHDA)-induced Caenorhabditis elegans models of PD. 23 However, SWE must be tested in rodent-based models to add its translational value. Therefore, we planned to investigate the neuroprotective effect of SWE against lipopolysaccharide (LPS)-induced inflammation in C6 glial cells, rotenone-induced neuroinflammation, α-syn accumulation, and DAergic neurodegeneration in a mouse model of PD.…”

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confidence: 99%

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Neuroprotective Effect of Swertiamarin in a Rotenone Model of Parkinson’s Disease: Role of Neuroinflammation and Alpha-Synuclein Accumulation

Sharma

Malim

Goswami

et al. 2022

ACS Pharmacol. Transl. Sci.

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Parkinson’s disease (PD) is a progressive neurodegenerative disease with no permanent cure affecting around 1% of the population over 65. There is an urgency to search for a disease-modifying agent with fewer untoward effects. PD pathology involves the accumulation of toxic alpha-synuclein (α-syn) and neuronal inflammation leading to the degeneration of dopaminergic (DAergic) neurons. Swertiamarin (SWE), a well-studied natural product, possesses a strong anti-inflammatory effect. It is a secoiridoid glycoside isolated from Enicostemma littorale Blume. SWE showed a reversal effect on the α-syn accumulation in the 6-hydroxydopamine (6-OHDA)-induced Caenorhabditis elegans model of PD. However, there are no reports in the literature citing the effect of SWE as a neuroprotective agent in rodents. The present study aimed to evaluate the anti-inflammatory activity of SWE against lipopolysaccharide (LPS)-induced C6 glial cell activation and its neuroprotective effect in the intrastriatal rotenone mouse PD model. SWE treatment showed a significant reduction in interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels in LPS-induced C6 glial cell activation. Further, our studies demonstrated the suppression of microglial and astroglial activation in substantia nigra (SN) after administration of SWE (100 mg/kg, intraperitoneally) in a rotenone mouse model. Moreover, SWE alleviated the rotenone-induced α-syn overexpression in the striatum and SN. SWE ameliorated the motor impairment against rotenone-induced neurotoxicity and mitigated the loss of DAergic neurons in the nigrostriatal pathway. Therefore, SWE has the potential to develop as an adjunct therapy for PD, but it warrants further mechanistic studies.

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Section: ■ Results and Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Neuroprotective Effect of Swertiamarin in a Rotenone Model of Parkinson’s Disease: Role of Neuroinflammation and Alpha-Synuclein Accumulation

Sharma

Malim

Goswami

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…This suggests that NKT can bind tightly to MAPK3 protein and reduce its expression. Studies have shown that MAPK is an important transducer of signals from the surface of the cell to the inside of the nucleus and can be activated by a variety of substances such as α‐syn and ROS, and plays an important role in the early inflammatory response of PD (Pandey et al, 2021). Activated by α‐syn, MAPK can cause the translocation of the transcription factor NF‐κB from the cytoplasm to the nucleus, further aggravating the neuroinflammatory response of PD (Chen et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…(b) PPI network and topology analysis of potential targets Through observation, it was found that ALB protein and MAPK1, MAPK3, and MAPK14 proteins of the MAPK family are closely related to NKT. In addition, literature reviews found that MAPK had a close relationship with the neuroinflammation of PD(Pandey, Shukla, Trivedi, Khan, & Pandey, 2021). Therefore, to further clarify the activity mode of NKT at the molecular level, we selected three proteins of the MAPK family for molecular docking with NKT.…”

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confidence: 99%

Nootkatone alleviates rotenone‐induced Parkinson's disease symptoms through activation of the PI3K/Akt signaling pathway

Yao

Bian

et al. 2022

Phytotherapy Research

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Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Nootkatone (NKT) has been shown to have neuroprotective, anti‐inflammatory, and antioxidant effects and in this study, we systematically studied the efficacy and mechanism of action of NKT in rotenone (ROT)‐induced PD rats. Firstly, through behavioral experiments and brain tissue staining, we found that NKT alleviated behavioral dysfunction and protected dopaminergic neurons associated with ROT‐induced PD rats. Next, target prediction, protein–protein interaction (PPI), Gene Ontology (GO), and pathway enrichment analyses were used to obtain potential targets, specific biological processes, and molecular mechanisms of NKT for the potential treatment of PD. Furthermore, we also applied molecular docking to predict the binding capacity of NKT and related targets. Additionally, in vivo experiments confirmed that NKT could inhibit the expression of Mitogen‐activated protein kinase 3 (MAPK3) by activating the PI3K/Akt signaling pathway, reducing neuroinflammation, and ultimately ameliorating ROT‐induced PD symptoms. Taken together, the results of the study provide a clear explanation for the remission of PD symptoms by NKT, suggesting that it may be a promising candidate for the treatment of PD.

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“…Alternate mechanisms of action include neuroprotection offered by traditional medicinal plants through enhancing endogenous antioxidant enzymes systems such as SKN-1/Nrf2 activation via the MAPK pathway in a Caenorhabditis elegans model of PD [188]. More recent studies have implicated a key role of soluble epoxide hydrolase (sEH) enzyme and its biological substrates such as eicosatrienoic (EETs) and epoxydocosapentaenoic (EDPs) acids in the regulation of neuroinflammation [189].…”

Section: Bioactive Natural Herbal Extractsmentioning

confidence: 99%

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

Leathem

Ortiz

Dennis

et al. 2022

IJMS

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.

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Swertiamarin from Enicostemma littorale, counteracts PD associated neurotoxicity via enhancement α-synuclein suppressive genes and SKN-1/NRF-2 activation through MAPK pathway

Cited by 12 publications

References 48 publications

Neuroprotective Effect of Swertiamarin in a Rotenone Model of Parkinson’s Disease: Role of Neuroinflammation and Alpha-Synuclein Accumulation

Neuroprotective Effect of Swertiamarin in a Rotenone Model of Parkinson’s Disease: Role of Neuroinflammation and Alpha-Synuclein Accumulation

Nootkatone alleviates rotenone‐induced Parkinson's disease symptoms through activation of the PI3K/Akt signaling pathway

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

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