title: Involvement of oxidative stress-activated JNK signaling in the methamphetamine-induced cell death of human SH-SY5Y cells.
abstract: Methamphetamine (METH) is one of the most commonly abused drugs that may result in neurotoxic damage. Many lines of evidence have revealed that oxidative stress plays an important role in METH-induced neurotoxic effects. In a previous study, it was demonstrated in human neuroblastoma SH-SY5Y cells that enhanced oxidative stress was related to METH-induced apoptosis. To evaluate which of the three major mitogen-activated protein (MAP) kinase signaling pathways are involved in the process, namely the extracellular signal-related kinases (ERK), the p38 MAP kinases (p38) and the Jun-N-terminal kinases (JNK), we performed a time-course assessment. This indicated that METH induced an increase in the phosphorylation of ERK and JNK, but not of p38. Moreover, a JNK-specific inhibitor, SP600125, partially but significantly rescued METH-induced cell death, while PD98059 (an ERK kinase inhibitor) and SB203580 (a p38 inhibitor) had no protective effect. We also found that vitamin E (Vit E) prevented METH-induced JNK phosporylation and SP600125 inhibited METH-induced c-Jun phosphorylation. Furthermore, METH-activated caspase-3 activity was significantly repressed by Vit E and in SP600125 treated cells. We suggest that the oxidative stress-activated JNK signaling pathway is involved in METH-induced cell death.
authors.affiliation: Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan 112, Republic of China.
authors.forename: Sheng-Fan
authors.initials: SF
authors.lastname: Wang
authors.forename: Jiin-Cherng
authors.initials: JC
authors.lastname: Yen
authors.forename: Pen-Hui
authors.initials: PH
authors.lastname: Yin
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008694:Methamphetamine / Q000633:toxicity*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000873:Anthracenes; D000975:Antioxidants; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D014810:Vitamin E; C432165:pyrazolanthrone; D008694:Methamphetamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one