S-ketamine ameliorates post-stroke depression in mice via attenuation of neuroinflammation, synaptic restoration, and BDNF pathway activation

The available therapeutic options for post-stroke depression patients are limited. Although SSRIs are the most commonly prescribed antidepressants, their slow onset of action and the higher risk of adverse effects or contraindications have led to an urgent need to develop fast-acting and highly specific antidepressants tailored to the needs of PSD patients. Therefore, ketamine has drawn attention. While ketamine has been shown to exert rapid antidepressant effects in numerous studies, whether it can ameliorate PSD remains unclear, and the molecular and cellular mechanisms underlying its therapeutic action in PSD are largely elusive. In this study, we used a PSD preclinical model induced by photothrombosis and chronic restraint stress to investigate the effects of S-ketamine. The present study demonstrates that a single acute intraperitoneal injection of 10 mg/kg S-ketamine on the first day after PSD significantly alleviates depressive-like behaviours in PSD mice. In addition, this improvement was maintained for at least five consecutive days. Mechanistically, S-ketamine reduced pro-inflammatory cytokines in the medial prefrontal cortex (mPFC), mitigated synaptic damage (evidenced by increased dendritic spine density, SYP, and PSD-95 expression). Furthermore, S-ketamine treatment upregulated the expression of brain-derived neurotrophic factor (BDNF), tropomyosin related kinase B (TrkB), phosphorylated serine/threonine-specific protein kinase B (p-Akt), phosphorylated extracellular signal–regulated kinase (p-Erk), phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII), and phosphorylated cAMP response element binding protein (p-CREB). Overall, S-ketamine shows promise for PSD treatment through its anti-inflammatory, synaptic enhancing, and BDNF pathway modulating effects. This research enhances our understanding of the pathological mechanisms underlying PSD and provides new therapeutic insights for its treatment.