Carbon monoxide offers neuroprotection from hippocampal cell damage induced by recurrent febrile seizures through the PERK-activated ER stress pathway

•Plasma CO level raised in a rat model of recurrent febrile seizures (FS).•Increased hippocampal cell damage and apoptosis in FS rats is attenuated by Hemin.•Increased p-PERK and p-eIF2α in FS rats is blocked by ZnPP-IX and enhanced by Hemin.•CO is neuroprotective in FS-induced hippocampal damage via the PERK-ER stress pathway. Carbon monoxide (CO) is neuroprotective in various models of brain injury, but the precise mechanisms for this are yet to be established. In the present study, using a rat model of recurrent febrile seizures (FSs), we found an increase in plasma CO, evidence of neuronal damage and apoptosis, an increase in the expression of the endoplasmic reticulum stress (ERS) marker glucose-regulated protein 78 (GRP78) and C/EBP homologous binding protein (CHOP), and an increase in phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK)/eukaryotic translation initiation factor 2 alpha (p-eIF2α) in the hippocampus after 10 FSs. Administration of Hemin (a CO donor) in FS rats alleviated the neuronal damage, reduced neuronal apoptosis, upregulated GRP78 expression, decreased CHOP, and increased p-PERK and p-eIF2α expression in the hippocampus, compared to FS control rats. In contrast, treating FS rats with ZnPP-IX (a CO synthase inhibitor) aggravated the neuronal damage, enhanced neuronal apoptosis, downregulated GRP78 expression, increased CHOP, and decreased p-PERK and p-eIF2α expression, compared to FS control rats. These results suggest that endogenous CO limits the neuronal damage induced by recurrent FSs, through the PERK-activated ERS pathway.