Inhibition of protein kinase C protects against paraoxon-mediated neuronal cell death
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- 作者：Feng Tian ; Xuan Wu ; Hongan Pan ; Hong Jiang ; Yu-Liang Kuo ; Ann M. Marini
- 关键词：Paraoxon ; PKC ; Neurotoxicity ; Neuroprotection ; Cerebellar granule cell neurons ; Pretreatment/post-treatment
- 刊名：Neurotoxicology
- 出版年：2007
- 出版时间：July 2007
- 年：2007
- 卷：28
- 期：4
- 页码：843-849
- 全文大小：336 K
文摘
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.