title: Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death.
abstract: 3-Hydroxykynurenine (3-HK), an endogenous tryptophan metabolite, is known to have toxic effects in brain. However, the molecular mechanism of the toxicity has not been well identified. In this study, we investigated the involvement of MAPK/extracellular signal-regulated kinase (ERK) in the 3-HK-induced neuronal cell damage. Our results showed that 3-HK induced apoptotic neuronal cell death and ERK phosphorylation occurred during cell death. Inhibition of ERK activation using PD98059 considerably increased cell death. Furthermore, cell death was preceded by mitochondrial malfunction including collapse of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release from mitochondria to the cytosol. Interestingly, inhibition of ERK dramatically increased mitochondrial malfunction, and enhanced caspase activation, resulting in enhanced neuronal cell death. Thus, our results show that ERK plays a protective role by maintaining mitochondrial function and regulating caspase activity under conditions of cellular stress.
authors.affiliation: Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, South Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Bach
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Chae
authors.forename: Sang Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Joo
authors.forename: Se Hoon
authors.initials: SH
authors.lastname: Choi
authors.forename: Kyung Yong
authors.initials: KY
authors.lastname: Kim
authors.forename: Won Bok
authors.initials: WB
authors.lastname: Lee
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Kim
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; C005045:3-hydroxykynurenine; D007737:Kynurenine; D020928:Mitogen-Activated Protein Kinases