title: Salubrinal, ER stress inhibitor, attenuates kainic acid-induced hippocampal cell death.
abstract: Kainic acid (KA)-induced neuronal death is closely linked to endoplasmic reticulum (ER) and mitochondrial dysfunction. Parkin is an ubiquitin E3 ligase that mediates the ubiquitination of the Bcl-2 family of proteins and its mutations are associated with neuronal apoptosis in neurodegenerative diseases. We investigated the effect of salubrinal, an ER stress inhibitor, on the regulation of ER stress and mitochondrial apoptosis induced by KA, in particular, by controlling parkin expression. We showed that salubrinal significantly reduced seizure activity and increased survival rates of mice with KA-induced seizures. We found that salubrinal protected neurons against apoptotic death by reducing expression of mitochondrial apoptotic factors and elF2α-ATF4-CHOP signaling proteins. Interestingly, we showed that salubrinal decreased the KA-induced parkin expression and inhibited parkin translocation to mitochondria, which suggests that parkin may regulate a cross-talk between ER and mitochondria. Collectively, inhibition of ER stress attenuates mitochondrial apoptotic and ER stress pathways and controls parkin-mediated neuronal death following KA-induced seizures.
authors.affiliation: Department of Neurosurgery, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea.
authors.forename: Jung Soo
authors.initials: JS
authors.lastname: Kim
authors.forename: Rok Won
authors.initials: RW
authors.lastname: Heo
authors.forename: Hwajin
authors.initials: H
authors.lastname: Kim
authors.forename: Chin-Ok
authors.initials: CO
authors.lastname: Yi
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Shin
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Han
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002934:Cinnamates / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011897:Random Allocation; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016019:Survival Analysis; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D002934:Cinnamates; D018696:Neuroprotective Agents; C496827:salubrinal; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D013890:Thiourea; D007608:Kainic Acid
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