H2S inhibits LiCl/pilocarpine-induced seizures and promotes neuroprotection by regulating TRPV2 expression via the AC3/cAMP/PKA pathway

It is widely acknowledged that epilepsy is a neurological disorder characterized by recurrent and atypical neuronal discharges, resulting in transient dysfunction within the brain. The protective role of hydrogen sulfide (H2S) in epilepsy has been elucidated by recent studies, but the underlying mechanisms remain poorly understood. To investigate this, the concentration of H2S was measured by spectrophotometry and a fluorescent probe in LiCl/Pilocarpine (LiCl/Pilo)-induced seizures in rats. The localization of proteins was examined using immunofluorescence. Electroencephalogram and behavioral tests were employed to evaluate the occurrence of seizures. Neuropathological changes in the hippocampus were examined by hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy. Through proteomics and bioinformatics analysis, we identified the differential proteins in the hippocampus of rats following H2S intervention. Protein changes were detected through western blotting. The results showed that H2S treatment significantly alleviated seizures and minimized post-seizures neurological damage in rats. Proteomics analysis revealed adenylate cyclase 3 (AC3) as a protein potentially targeted by H2S. Moreover, the AC3 activator forskolin reversed the downregulation effect of H2S on the AC3/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/transient receptor potential vanilloid 2 (TRPV2) signaling pathway. In conclusion, H2S targets and downregulates the expression of AC3, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate the expression of TRPV2 in LiCl/Pilo-induced seizures, ultimately leading to seizure inhibition and neuroprotection. Exogenous hydrogen sulfide (H2S) can regulate the expression of TRPV2 through the AC3/cAMP/PKA pathway, which ultimately leads to the attenuation of seizures and the promotion of neuroprotection. These significant findings indicate that H2S could potentially serve as an effective treatment for reducing neurological damage caused by epilepsy. [Display omitted] •Proteomic analysis of epileptic rats' hippocampus reveals AC3 as a targeted protein by exogenous H2S.•Exogenous H2S affects the expression of AC3, cAMP, PKA, p-PKA, and TRPV2 in the hippocampus of epileptic rats.•Exogenous H2S inhibits seizures and protects the hippocampal nerve by downregulating TRPV2 expression via the AC3/cAMP/PKA.