title: Carbon monoxide offers neuroprotection from hippocampal cell damage induced by recurrent febrile seizures through the PERK-activated ER stress pathway.
abstract: 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.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Peking University First Hospital, PR China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Yi
authors.affiliation: Department of Pediatrics, Peking University First Hospital, PR China. Electronic address: qinjiong@gmail.com.
authors.forename: Jiong
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Pediatrics, Peking University First Hospital, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Peking University First Hospital, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, PR China.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002248:Carbon Monoxide / Q000097:blood*; D059865:Endoplasmic Reticulum Stress; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000473:pathology*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D003294:Seizures, Febrile / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D002248:Carbon Monoxide; D019892:eIF-2 Kinase
keywords: Carbon monoxide; Endoplasmic reticulum stress; Febrile seizure; Hippocampus; Neuronal damage; PERK