Valproic acid attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-pyroptosis pathways

Ischemic stroke is the third most common cause of death and the leading cause of disability worldwide in adults. The antiepileptic drug valproic acid (VPA) was reported to protect cerebral ischemia/reperfusion injury. However, the action mechanism of VPA in cerebral ischemia/reperfusion injury has not been fully understood. We explored the action mechanism of VPA in vivo and in vitro. Gerbils were subjected to transient global cerebral ischemic–reperfusion injury, and hippocampal neuron injury was treated with oxygen-glucose deprivation in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. Histopathological examinations and western blot were performed to evaluate the pyroptosis of neurons. The results showed that VPA attenuated the cognitive dysfunction, pyroptosis of the gerbils suffer from ischemic–reperfusion injury and decreased hippocampal neurons pyroptosis induced by oxygen-glucose deprivation in vitro. In addition, western blot and real-time PCR analysis revealed that VPA modulated the protein expression of apoptosis repressor with caspase recruitment domain (ARC), caspase-1 and IL-1β/IL-18. Our results suggested that VPA alleviated ischemic/reperfusion injury-mediated neuronal impairment by anti-pyroptotic effects. •Valproic acid could attenuate the cognitive dysfunction in I/R gerbils.•Valproic acid alleviated neuronal impairment by anti-pyroptotic effects.•The anti-pyroptotic effects of VPA may be through ARC-caspase-1 pathway.