title: Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway.
abstract: Kynurenic acid (KYNA), a tryptophan metabolite in the kynurenine pathway, is protective against various insults. However, the molecular mechanism of this protective effect has not been identified. In this study, we examined the protective effects of KYNA against 1-methyl-4-phenylpyridinium (MPP(+)), the best-characterized toxin inducing pathological changes resembling Parkinson's disease (PD), using SH-SY5Y and SK-N-SH human neuroblastoma cells. Pre-treatment of KYNA attenuated MPP(+)-induced neuronal cell death in SH-SY5Y and SK-N-SH cells. MPP(+)-induced cell death was preceded by increases in Bax expression and mitochondrial dysfunction, such as collapse of mitochondrial membrane potential (DeltaPsi(m)), release of cytochrome c from mitochondria into the cytoplasm, and increases in caspase-9/-3 activities. KYNA effectively inhibited all of these mitochondrial apoptotic processes. Our results indicate that KYNA plays a protective role by down-regulating Bax expression and maintaining mitochondrial function in MPP(+)-induced neuronal cell death, and suggest that KYNA may have therapeutic potential in PD.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Dongjak-Ku, Seoul, Republic of Korea.
authors.forename: Do Yeon
authors.initials: DY
authors.lastname: Lee
authors.forename: Kyu-Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Yoo Hun
authors.initials: YH
authors.lastname: Noh
authors.forename: Do Hee
authors.initials: DH
authors.lastname: Kim
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Cho
authors.forename: Ok Ja
authors.initials: OJ
authors.lastname: Yoon
authors.forename: Won Bok
authors.initials: WB
authors.lastname: Lee
authors.forename: Kyung Yong
authors.initials: KY
authors.lastname: Kim
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Kim
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D007736:Kynurenic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine