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SIRT1 Activation by Polydatin Alleviates Oxidative Damage and Elevates Mitochondrial Biogenesis in Experimental Diabetic Neuropathy

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Abstract

Mitochondrial dysfunction has been implicated as a one of the major factors linked to the development of painful diabetic neuropathy (DN). Several studies have demonstrated that sirtuin (SIRT1) activation recuperates nerve function by activating mitochondrial biogenesis. Polydatin, a resveratrol glycoside, has been explored to improve mitochondrial function via SIRT1 activation. However, the neuroprotective effects of polydatin in DN remain elusive. In this study, polydatin (25 and 50 mg/kg, oral) was administered for last 2 weeks of 8-week study to diabetic Sprague–Dawley rats weighing 250–300 g (post 6-weeks of streptozotocin 55 mg/kg, intraperitoneal). Treatment with polydatin significantly attenuated mechanical and thermal hyperalgesia in diabetic rats. Treated diabetic rats also showed improvement in motor/sensory nerve conduction velocities and nerve blood flow. For in vitro studies, Neuro2a cells were exposed to high-glucose (30 mM) condition to simulate short-term hyperglycemia. Polydatin was evaluated for its role in SIRT1 and Nrf2 activation at a dose of 5, 10, and 20 µM concentrations. Polydatin exposure normalized the mitochondrial superoxides, membrane potentials and improved neurite outgrowth in high-glucose-exposed Neuro2a cells. Increased SIRT1 activation by polydatin resulted in peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis. SIRT1 activation also facilitated Nrf2-directed antioxidant signaling. Study results inferred that decline in mitochondrial biogenesis and oxidative function in diabetic rats and high-glucose-exposed Neuro2a cells, could be counteracted by polydatin administration, postulated via enhancing SIRT1 and Nrf2 axis.

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Acknowledgements

Authors sincerely acknowledge the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for providing financial support in carrying out this work.

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MS Preethi Bheereddy (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India-500037), performed studies, evaluated data, prepared figures and wrote manuscript; Dr Veera Ganesh Yerra (Postdoctoral Fellow at Keenan Research Centre for Biomedical Sciences, St. Michael's Hospital, Toronto, Canada), performed studies, evaluated data, prepared figures and wrote manuscript; Mr Anil Kumar Kalvala (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India-500037), performed studies, evaluated data, prepared figures and wrote manuscript; Ms Bhoomika S (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Telangana, India-500037), performed studies, evaluated data, prepared figures and reviewed manuscript; Dr Ashutosh Kumar (Department of Pharmacology and Toxicology, NIPER-HYDERABAD, Balanagar, Telangana, India-500037), designed this work, evaluated data and wrote and reviewed manuscript.

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Correspondence to Ashutosh Kumar.

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Research Involving Human and Animals Participants

This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted. (Institutional Animal Ethics Committee (IAEC)—NIPER-Hyderabad, India + Protocol No: NIP/8/2016/PC/213).

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Bheereddy, P., Yerra, V.G., Kalvala, A.K. et al. SIRT1 Activation by Polydatin Alleviates Oxidative Damage and Elevates Mitochondrial Biogenesis in Experimental Diabetic Neuropathy. Cell Mol Neurobiol 41, 1563–1577 (2021). https://doi.org/10.1007/s10571-020-00923-1

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