Losartan's regulation of PI3K/AKT signaling underlies its combined anti-seizure and antidepressant effects in epileptic rats.

OBJECTIVE: To investigate whether losartan alleviates seizures and depression-like behaviors in epileptic rats, and to explore its potential mechanisms involving the PI3K/AKT signaling pathway and hippocampal neuroprotection. METHODS: Status epilepticus (SE) was induced in Sprague-Dawley rats using lithium-pilocarpine. Post-SE rats were randomized to receive daily intraperitoneal injections of either losartan (60 mg/kg) or saline for 20 days. A control group was also set. Seizure frequency was monitored over a 24-hour period post-intervention. Depression-like behaviors were evaluated through weekly body weight gain and the sucrose preference test (SPT). Molecular changes in the hippocampus were assessed via RT-qPCR, western blot, and immunofluorescence staining for PI3K/AKT pathway components and apoptosis markers. RESULTS: Losartan treatment significantly decreased the frequency of seizures in SE rats. Concurrently, it ameliorated depression-like phenotypes, evidenced by greater weight gain and a higher sucrose preference rate. At the molecular level, losartan upregulated hippocampal expression of PI3K, the p-AKT/AKT ratio, and the anti-apoptotic protein Bcl-2, while downregulating pro-apoptotic factors Bax, Caspase-3, and Cleaved-Caspase-3. This indicates a reversal of SE-induced suppression of the PI3K/AKT cascade. Immunofluorescence analysis further confirmed that losartan significantly mitigated SE-associated hippocampal neuronal loss. CONCLUSION: Losartan may attenuate both seizures and depression-like behaviors in epileptic rats by activating the hippocampal PI3K/AKT signaling pathway and inhibiting neuronal apoptosis. These results highlight its potential as an adjunctive therapy for epilepsy with comorbid depression.