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Resveratrol Attenuates Chronic Unpredictable Mild Stress-Induced Alterations in the SIRT1/PGC1α/SIRT3 Pathway and Associated Mitochondrial Dysfunction in Mice

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Abstract

Environmental challenges, specifically chronic stress, have long been associated with neuropsychiatric disorders, including anxiety and depression. Sirtuin-1 (SIRT1) is a NAD+-dependent deacetylase that is widely distributed in the cortex and is involved in stress responses and neuropsychiatric disorders. Nevertheless, how chronic stress modulates the SIRT1 pathway and associated signaling remains unclear. In this study, we first explored the impact of chronic unpredictable mild stress (CUMS) on the SIRT1/PGC1α/SIRT3 pathway, on GABAergic mechanisms, and on mitophagy, autophagy and apoptosis in mice. We also asked whether activation of SIRT1 by resveratrol (RSV) can attenuate CUMS-induced molecular and behavioral alterations. Two-month-old C57/BL6J mice were subjected to three weeks of CUMS and one week of RSV treatment (30 mg/kg; i.p.) during the third week of CUMS. CUMS caused downregulation of the SIRT1/PGC1α/SIRT3 pathway leading to impaired mitochondrial morphology and function. CUMS also resulted in a reduction in numbers of parvalbumin-positive interneurons and increased oxidative stress leading to reduced expression of autophagy- and mitophagy-related proteins. Strikingly, activation of SIRT1 by RSV ameliorated expression of SIRT1/PGC1α/SIRT3, and also improved mitochondrial function, GABAergic mechanisms, mitophagy, autophagy and apoptosis. RSV also rescued CUMS-induced anxiety-like and depressive-like behavior in mice. Our results raise the compelling possibility that RSV treatment might be a viable therapeutic method of blocking stress-induced behavioral alterations.

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Data Availability

All data generated or analyzed in this study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Natural Science Foundation of China (31871170, 32170950, and 31970915), and the Natural Science Foundation of Guangdong Province (2021A1515010804 and 2023A1515010899).

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Author notes

  1. Sidra Tabassum and Afzal Misrani contributed equally to this work.

Authors and Affiliations

  1. South China Normal University-Panyu Central Hospital Joint Laboratory of Translational Medical Research, Panyu Central Hospital, Guangzhou, 511400, China

    Sidra Tabassum, Afzal Misrani, Hui-xian Huang & Cheng Long

  2. School of Life Sciences, South China Normal University, Guangzhou, 510631, China

    Sidra Tabassum, Afzal Misrani, Hui-xian Huang & Cheng Long

  3. Department of Cardiology, Panyu Central Hospital, Guangzhou, 511400, China

    Zai-yong Zhang

  4. Cardiovascular Institute of Panyu District, Guangzhou, 511400, China

    Zai-yong Zhang

  5. Department of Neurology, Panyu District Central Hospital, Guangzhou, 511400, China

    Qiao-wei Li

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  1. Sidra Tabassum
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  2. Afzal Misrani
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Contributions

Sidra Tabassum, project initiation, experimental design, immunostaining, behavior, statistical analysis, and manuscript writing; Afzal Misrani, western blotting, TEM analysis, and manuscript writing; Hui-xian Huang, patch clamp recording; Zai-yong Zhang, critical review of the manuscript; Qiao-wei Li, supervision, Cheng Long, funding acquisition and supervision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Cheng Long.

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Ethics Statement

This study was approved by the South China Normal University Institutional Review Boards. The use of animals in experiments was approved by the Institutional Animal Care and Use Committee (IACUC) and followed National Institutes of Health (NIH) guidelines.

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Tabassum, S., Misrani, A., Huang, Hx. et al. Resveratrol Attenuates Chronic Unpredictable Mild Stress-Induced Alterations in the SIRT1/PGC1α/SIRT3 Pathway and Associated Mitochondrial Dysfunction in Mice. Mol Neurobiol 60, 5102–5116 (2023). https://doi.org/10.1007/s12035-023-03395-8

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