Blockade of the translocation and activation of c-Jun N-terminal kinase 3 (JNK3) attenuates dopaminergic neuronal damage in mouse model of Parkinson's disease.
Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal death in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). JNK3, the only neural-specific isoform, may play an important role in mediating the neurotoxic effects of MPTP in dopaminergic neuronal injury. To analyze the variation in JNK3 activation, the levels of phospho-JNK3 were measured at the various time points of occurrence of MPTP-induced lesions. In our study, we observed that during MPTP intoxication, two peaks of JNK3 activation appeared at 8 and 24h. To further define the mechanism of JNK3 activation and translocation, the antioxidant N-acetylcysteine (NAC), the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) were administered to the mice 30 min after each of the four MPTP injections. The results revealed that NAC clearly inhibited JNK3 activation during the early intoxication, whereas ketamine preferably attenuated JNK3 activation during the latter intoxication. DNQX had no significant effects on JNK3 activation during intoxication. Consequently, reactive oxygen species (ROS) and the NMDA receptor were closely associated with JNK3 activation following MPTP intoxication. NAC and ketamine exerted a preventive effect against MPTP-induced loss of tyrosine hydroxylase-positive neurons and suppressed the nuclear translocation of JNK3, suggesting that NAC and ketamine can prevent MPTP-induced dopaminergic neuronal death by suppressing JNK3 activation.
Pan
Jing
J
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, PR China.
Xiao
Qin
Q
Sheng
Cheng-Yu
CY
Hong
Zhen
Z
Yang
Hong-Qi
HQ
Wang
Gang
G
Ding
Jian-Qing
JQ
Chen
Sheng-Di
SD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000502:physiology; D017072:Neostriatum / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; C056723:FG 9041; D007649:Ketamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D048057:Mitogen-Activated Protein Kinase 10; D004298:Dopamine; D000111:Acetylcysteine