Exercise-induced Activation of SIRT1/BDNF/mTORC1 Signaling Pathway: A Novel Mechanism to Reduce Neuroinflammation and Improve Post-stroke Depression.

Background: Neuroinflammation and neurogenic disorders lead to depression in stroke patients. As, exercise intervention, a non-drug therapy, has been proven effective in post-stroke depression (PSD) patients. However, the underlying molecular mechanism by which exercise improves PSD still needs to be explored. Therefore, utilizing the mice model, this study aimed to observe the pathological changes in PSD and to investigate the mechanism by which exercise improves PSD symptoms.

Methods: A middle cerebral artery occlusion (MCAO)+chronic unpredictable mild stress (CUMS) method was used to establish the PSD mice model, and the model mice were subjected to exercise interventions. Behavior tests were conducted to validate changes in depression-like behaviors. Western blot and reverse transcription-polymerase chain reaction (RT-qPCR) analyses were used to evaluate the expression levels of silent information regulator factor 2-related enzyme 1 (SIRT1), brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in brain tissue. Enzyme linked immunosorbent assay (ELISA) analyses were performed to assess the effects of exercise on neuroinflammatory markers. Hematoxylin-Eosin (HE) and Nissl staining were used to examine exercise-induced histopathological change in the brain tissue. Furthermore, SIRT1 was knocked down using an adenovirus-mediated approach, and glial fibrillary acidic protein (GFAP) staining was used to determine the number of astrocytes in brain tissue.

Results: Exercise significantly alleviates the symptoms of neurological dysfunction in model mice (p < 0.01). Exercise decreased the immobile time of PSD mice (p < 0.05) and increased the total exploration distance and crossing area (p < 0.05). Furthermore, exercise significantly reduced inflammatory marker levels, such as interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and IL-1β (p < 0.05), and elevated anti-inflammatory factor IL-10 levels (p < 0.01). Moreover, exercise training alleviated inflammatory infiltration, increased the number of Nissl bodies (p < 0.05), and improved pathological changes in PSD mice. Additionally, exercise enhanced the expression levels of SIRT1, BDNF (p < 0.01), synaptophysin (Syn1), and postsynaptic density (PSD) 95 (p < 0.01), thereby improving synaptic plasticity and enhancing astrocyte activity (p < 0.05). Furthermore, compared to the model+exercise+con-shRNA group, SIRT1 knockdown inhibited protein expression in the mammalian target of rapamycin (mTOR) pathway (p < 0.05), reversing exercise-induced effects.

Conclusion: Exercise intervention reduces post-stroke depression-like behavior by activating SIRT1/BDNF/mTORC1 signaling pathway and reducing neuroinflammation. These findings provide insights into understanding the role of exercise in treating post-stroke depression and offer a theoretical basis for developing novel antidepressant strategies.