Post-stroke depression (PSD) is a prevalent mental health issue, and resveratrol (RES) has been implicated in its management. This study aimed to elucidate the impact of RES on PSD. A PSD rat model was established through middle cerebral artery occlusion and chronic unpredictable mild stress. Rats received RES via gavage, and depressive behaviors were evaluated through various measures. Cerebral infarction areas and brain tissue pathology were assessed using TTC and H&E staining. Levels of inflammatory factors (TNF-α/IL-1β/IL-6/IL-10), neurotransmitters (ACH/DA/5-HT/BDNF), and oxidative stress-related indicators (SOD/GSH-Px/MDA), along with the total Nrf2/C-Nrf2/N-Nrf2/HO-1 proteins, were analyzed. The role of the Nrf2/HO-1 pathway was investigated by co-treating rats with RES and either an Nrf2 pathway specific inhibitor (ML385) or activator (dimethyl fumarate). PSD rats exhibited depressive behaviors, disrupted neurotransmitter levels, and oxidative stress markers. RES treatment effectively alleviated these symptoms and activated the Nrf2/HO-1 pathway in PSD rat brain tissues. Co-administration of ML385 attenuated the beneficial effects of RES in PSD rats. Altogether, RES mitigates depressive behaviors, improves cognitive dysfunction, and reduces oxidative stress and inflammatory response in PSD rats. These effects are mediated through the activation of the Nrf2/HO-1 pathway, suggesting RES as a potential therapeutic agent for PSD-related cognitive impairment.
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