Inhibition of protein kinase C protects against paraoxon-mediated neuronal cell death.
Paraoxon, the active metabolite of parathion, is an acetylcholinesterases (AChE) inhibitor that kills cultured cerebellar granule cell neurons via an apoptotic mechanism. Protein kinase C is an enzyme with diverse functions but its role in paraoxon-induced cell death is unknown. We show that a neurotoxic concentration of paraoxon increases PKC phosphorylation. We tested whether PKC is involved in paraoxon-induced neuronal cell death by using the PKC activator, phorbol 12-myristate 13-acetate (TPA). TPA increases PKC activity and enhances the neurotoxic effect of paraoxon by 28%. In sharp contrast, addition of the PKC inhibitor Ro-31-8220 protects more than 30% neurons that would otherwise die from paraoxon-induced neuronal cell death in either a pretreatment or post-treatment paradigm and markedly reduces phospho-PKC pan levels. We also show that the pretreatment of Ro-31-8220 blocks paraoxon-induced caspase-3 activity completely. These results suggest that activation of protein kinase C is required for paraoxon neurotoxicity.
Tian
Feng
F
Department of Neurology and Program in Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Wu
Xuan
X
Pan
Hongan
H
Jiang
Hong
H
Kuo
Yu-Liang
YL
Marini
Ann M
AM
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010261:Paraoxon / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D010261:Paraoxon