Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway.
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.
Lee
Do Yeon
DY
Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Dongjak-Ku, Seoul, Republic of Korea.
Lee
Kyu-Sun
KS
Lee
Hyun Jung
HJ
Noh
Yoo Hun
YH
Kim
Do Hee
DH
Lee
Jun Young
JY
Cho
Soo Hyun
SH
Yoon
Ok Ja
OJ
Lee
Won Bok
WB
Kim
Kyung Yong
KY
Chung
Yoon Hee
YH
Kim
Sung Su
SS
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*
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