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Wedelolactone Mitigates Parkinsonism Via Alleviating Oxidative Stress and Mitochondrial Dysfunction Through NRF2/SKN-1

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Abstract

Parkinsonism is an age-associated neurodegenerative disorder characterized by aggregation of α-synuclein (α-syn) protein in the substantia nigra region, degeneration of dopaminergic neurons, and deregulated lipid metabolism. Currently, only symptomatic relief has been provided by FDA-approved therapeutic approaches for Parkinson’s disease (PD). The present study aims to evaluate the potential of wedelolactone (WDL), a natural occurring coumestan found in Eclipta alba to mitigate the parkinsonism in Caenorhabditis elegans disease model. In the present studies, supplementation with 37.5 μM WDL exhibited a reduction in the level of α-syn in an age-dependent manner (22% at day 5, p < 0.05; and 16% at day 10, p < 0.001, n = 30), along with improvement in neuronal health through basal movement, and elevated the dopamine levels evident through 1-nonanol repulsion results in wild-type and diseased worms. Moreover, WDL augmented the mitochondrial health in wild-type, PD-diseased, and mev-1 mutant worms that establish the inherent activity of WDL in the alleviation of oxidative stress. Furthermore, WDL supplementation significantly decreases the neutral lipid and triglyceride level and also alleviates protein carbonyl level in PD disease condition. The overall investigation will provide a pioneer to the future insights of PD research related to plant-based drugs. qPCR studies after WDL supplementation revealed alteration of genes involved in the regulation of various stress-responsive (sod-5, gst-4, skn-1), α-syn-suppressing (lrk-1, ymel-1, lagr-1, grk-1), and mitochondrial (pink-1) genes. All together, these findings support that the WDL is a promising candidate to combat age-related multi-factorial PD pathology associated with protein misfolding and accumulation. The results provide sufficient information in the development of therapeutic medicines from natural products for improving the health.

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Acknowledgments

The authors are highly grateful to the Caenorhabditis Genetics Centre (CGC), Minneapolis, MN, USA, which is funded by the NIH, National Centre for Research Resources (USA), for providing the C. elegans strains. The authors are grateful to the Director, CSIR–Central Institute of Medicinal and Aromatic Plants, Lucknow, India, for his valuable support.

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  1. Shruti Sharma and Shalini Trivedi contributed equally to this work.

Authors and Affiliations

  1. Ageing Biology Lab Microbial Technology & Nematology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Near Kukrail Picnic Spot, Lucknow, 226015, India

    Shruti Sharma, Shalini Trivedi, Taruna Pandey, Sachin Ranjan, Mashu Trivedi & Rakesh Pandey

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  1. Shruti Sharma
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Correspondence to Rakesh Pandey.

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Sharma, S., Trivedi, S., Pandey, T. et al. Wedelolactone Mitigates Parkinsonism Via Alleviating Oxidative Stress and Mitochondrial Dysfunction Through NRF2/SKN-1. Mol Neurobiol 58, 65–77 (2021). https://doi.org/10.1007/s12035-020-02080-4

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