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Previous studies have demonstrated that excessive free radicals play an essential role in the initiation and progression of epilepsy and that a novel exogenous free radical scavenger edaravone (Ed) exerts some neuroprotective effects on seizure‐induced neuronal damage. The purpose of this study was to elucidate the possible molecular mechanisms of Ed associated with procaspase‐3 denitrosylation and activation through the FasL‐Trx2 pathway in seizures rats. In this study, we investigated the effects of Ed on the regulation of the combination of Fas ligand/Fas receptor and the major components of the death‐inducing signaling complex (DISC) in the hippocampus of kainic acid (KA)‐treated Sprague Dawley (SD) rats. Treatment with Ed can attenuate the increased expression of FasL induced by KA and prevent procaspase‐3 denitrosylation and activation via suppression of the FasL‐Trx2 signaling pathway, which alleviates the neuronal damage in seizures. These results provide experimental evidence that Ed functions by preventing the denitrosylation and activation of procaspase‐3 and that Ed acts as a therapeutic option for epilepsy.

Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies.