Effect of N-methyl-D-aspartate (NMDA) receptor antagonists on alpha-synuclein-evoked neuronal nitric oxide synthase activation in the rat brain

Pharmacol Rep. Nov-Dec 2009;61(6):1078-85. doi: 10.1016/s1734-1140(09)70170-7.

Abstract

alpha-Synuclein (ASN), a small presynaptic protein that is abundant in the brain, is implicated in the pathogenesis of neurodegenerative disorders including Parkinson's and Alzheimer's disease. The central domain of alpha-synuclein, the non-amyloid beta component of the Alzheimer's disease amyloid (NAC) is probably responsible for its toxicity. However, the molecular mechanism of alpha-synuclein action remains largely elusive. The present study examined the effect of alpha-synuclein and the NAC peptide on nitric oxide synthase (NOS) activity in rat brain cortical and hippocampal slices using a radiochemical technique. Moreover, nitrite levels in brain slices incubated in the presence of alpha-synuclein were measured using the Griess reaction. ASN and the NAC stimulated NOS activity by about 70% and 40%, respectively. beta-Synuclein, a homologous protein of ASN that lacks the NAC domain, had no effect on NOS activity. Under the same experimental conditions, alpha-synuclein increased nitrite levels by 27%. alpha-Synuclein and the NAC affected the activity of constitutive neuronal isoform of NOS, but had no impact on the endothelial or inducible NOS isoforms. The effect of alpha-synuclein and the NAC peptide on NOS activity was inhibited by MK-801 and APV, antagonists of the NMDA receptor. These results indicate that the NMDA receptor plays an important role in alpha-synuclein-evoked nitric oxide synthesis. We suggest that nitric oxide liberated by the over-activated neuronal isoform of NOS could react with superoxide to form peroxynitrite, which modulates the function of a variety of biomolecules including proteins, lipids, and DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Brain / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Dizocilpine Maleate / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Male
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase Type I / metabolism*
  • Nitrites / metabolism
  • Peptide Fragments / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • alpha-Synuclein / metabolism*
  • beta-Synuclein / metabolism

Substances

  • Excitatory Amino Acid Antagonists
  • Nitrites
  • Peptide Fragments
  • Receptors, N-Methyl-D-Aspartate
  • alpha-Synuclein
  • beta-Synuclein
  • Nitric Oxide
  • Dizocilpine Maleate
  • 2-Amino-5-phosphonovalerate
  • Nitric Oxide Synthase Type I