Haloperidol-induced neuronal apoptosis: role of p38 and c-Jun-NH(2)-terminal protein kinase.
We examined patterns and mechanisms of cell death induced by haloperidol. Cortical cell cultures exposed to 10-100 microM: haloperidol for 24 h underwent neuronal death without injuring glia. The degenerating neurons showed hallmarks of apoptosis, featuring cell body shrinkage, nuclear chromatin condensation and aggregation, nuclear membrane disintegration with intact plasma membrane, and prominent internucleosomal DNA fragmentation. Neither glutamate antagonists nor antioxidants prevented the haloperidol-induced neuronal apoptosis. The c-Jun-NH(2)-terminal protein kinase and p38 mitogen-activated protein kinase were activated within 1 h and were sustained over the next 3 h following exposure of cortical neurons to 30 microM haloperidol. Haloperidol-induced neuronal apoptosis was partially attenuated by 10-30 microM PD169316, a selective inhibitor of p38 mitogen-activated protein kinase. Inclusion of 1 microg/ml cycloheximide, a protein synthesis inhibitor, or 100 ng/ml insulin prevented activation of both kinases and subsequent neuronal death. The present study demonstrates that cortical neurons exposed to haloperidol undergo apoptosis depending on activation of p38 mitogen-activated protein kinase and c-Jun-NH(2)-terminal protein kinase sensitive to cycloheximide and insulin.
Noh
J S
JS
Department of Psychiatry and Behavioral Sciences, Institute for Medical Sciences, Ajou University School of Medicine, Kyungkido, Korea. jsnoh@madang.ajou.ac.kr
Kang
H J
HJ
Kim
E Y
EY
Sohn
S
S
Chung
Y K
YK
Kim
S U
SU
Gwag
B J
BJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity*; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000975:Antioxidants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D007093:Imidazoles; D007328:Insulin; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; D006220:Haloperidol