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

α-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 α-synuclein, the non-amyloid β component of the Alzheimer’s disease amyloid (NAC) is probably responsible for its toxicity. However, the molecular mechanism of α-synuclein action remains largely elusive. The present study examined the effect of α-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 α-synuclein were measured using the Griess reaction. ASN and the NAC stimulated NOS activity by about 70% and 40%, respectively. β-Synuclein, a homologous protein of ASN that lacks the NAC domain, had no effect on NOS activity. Under the same experimental conditions, α-synuclein increased nitrite levels by 27%. α-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 α-synuclein and the NAC peptide on NOS activity was inhibited by MK-801 and APV, antagonists of the NMDAreceptor. These results indicate that the NMDAreceptor plays an important role in α-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.