The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway.
Environmental exposure to the oxidant-producing herbicide paraquat has been implicated as a risk factor in Parkinson's disease. Although intraperitoneal paraquat injections in mice cause a selective loss of dopaminergic neurons in the substantia nigra pars compacta, the exact mechanism involved is still poorly understood. Our data show that paraquat induces the sequential phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the activation of caspase-3 and sequential neuronal death both in vitro and in vivo. These effects are diminished by the specific JNK inhibitor SP600125 and the antioxidant manganese(III) tetrakis (4-benzoic acid) porphyrin in vitro. Furthermore, JNK pathway inhibitor CEP-11004 effectively blocks paraquat-induced dopaminergic neuronal death in vivo. These results suggest that the JNK signaling cascade is a direct activator of the paraquat-mediated nigral dopaminergic neuronal apoptotic machinery and provides a molecular linkage between oxidative stress and neuronal apoptosis.
Peng
Jun
J
Buck Institute for Age Research, Novato, California 94945, USA.
Mao
Xiao Ou
XO
Stevenson
Fang Feng
FF
Hsu
Michael
M
Andersen
Julie K
JK
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000494:pharmacology; D006540:Herbicides / Q000494:pharmacology*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010269:Paraquat / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D000873:Anthracenes; D000975:Antioxidants; D016166:Free Radical Scavengers; D006540:Herbicides; D008665:Metalloporphyrins; D011954:Receptors, Dopamine; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010269:Paraquat