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

Biochem Biophys Res Commun. 2018 Jan 15;495(3):2165-2170. doi: 10.1016/j.bbrc.2017.12.088. Epub 2017 Dec 16.


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.

Keywords: 8-nitro-cGMP; H-Ras/ERK signaling; MPP(+); NO/ROS redox signaling; Neurotoxicity; nNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium*
  • Animals
  • Cells, Cultured
  • Cerebellum / drug effects
  • Cerebellum / metabolism*
  • Cerebellum / pathology
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Dose-Response Relationship, Drug
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Neurotoxins
  • Nitric Oxide / metabolism*
  • PC12 Cells
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / metabolism*
  • Rats
  • Reactive Oxygen Species / metabolism*


  • 8-nitroguanosine 3',5'-cyclic monophosphate
  • Neurotoxins
  • Reactive Oxygen Species
  • Nitric Oxide
  • Cyclic GMP
  • 1-Methyl-4-phenylpyridinium