Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons

摘要

Abstract To investigate the role of nitric oxide (NO)/reactive oxygen species (ROS) redox signaling in Parkinson's disease-like neurotoxicity, we used 1-methyl-4-phenylpyridinium (MPP + ) treatment (a model of Parkinson's disease). We show that MPP + -induced neurotoxicity was dependent on ROS from neuronal NO synthase (nNOS) in nNOS-expressing PC12?cells (NPC12?cells) and rat cerebellar granule neurons (CGNs). Following MPP + treatment, we found production of 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), a second messenger in the NO/ROS redox signaling pathway, in NPC12?cells and rat CGNs, that subsequently induced S -guanylation and activation of H-Ras. Additionally, following MPP + treatment, extracellular signal-related kinase (ERK) phosphorylation was enhanced. Treatment with a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor attenuated MPP + -induced ERK phosphorylation and neurotoxicity. In conclusion, we demonstrate for the first time that NO/ROS redox signaling via 8-nitro-cGMP is involved in MPP + -induced neurotoxicity and that 8-nitro-cGMP activates H-Ras/ERK signaling. Our results indicate a novel mechanism underlying MPP + -induced neurotoxicity, and therefore contribute novel insights to the mechanisms underlying Parkinson's disease. Highlights ? ROS from nNOS are involved in MPP + -induced cytotoxicity in nNOS-expressing PC12?cells and rat cerebellar granule neurons. ? 8-Nitro-cGMP, a downstream molecule in the NO/ROS redox signaling pathway, is involved in MPP + -induced neurotoxicity. ? Involvement of H-Ras/ERK signaling activated by 8-Nitro-cGMP was also demonstrated in MPP + -induced neurotoxicity.