Excitotoxicity and nitric oxide in Parkinson's disease pathogenesis.
A potential role for excitotoxic processes in Parkinson's disease (PD) has been strengthened by the recent observations that there appears to be a mitochondrially encoded defect in complex I activity of the electron transport chain. An impairment of oxidative phosphorylation will enhance vulnerability to excitotoxicity. Substantia nigra neurons possess N-methyl-D-aspartate receptors and there are glutamatergic inputs into the substantia nigra from both the cerebral cortex and the subthalamic nucleus. After activation of excitatory amino acid receptors, there is an influx of calcium followed by activation of neuronal nitric oxide (NO) synthase, which can then lead to the generation of peroxynitrite. Consistent with such a mechanism, studies of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in both mice and primates have shown that inhibition of neuronal NO synthase exerts neuroprotective effects. Studies utilizing excitatory amino acid receptor antagonists have been inconsistent in mice but show significant neuroprotective effects in primates. These results raise the prospect that excitatory amino acid antagonists for neuronal NO synthase inhibitors might be useful in the treatment of PD.
Beal
M F
MF
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D000818:Animals; D004579:Electron Transport; D006801:Humans; D020267:MPTP Poisoning; D008928:Mitochondria / Q000502:physiology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010300:Parkinson Disease / Q000209:etiology / Q000503:physiopathology*; D017470:Receptors, Glutamate / Q000502:physiology*
D017470:Receptors, Glutamate; D009569:Nitric Oxide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019001:Nitric Oxide Synthase; D016660:NAD(P)H Dehydrogenase (Quinone)