PT  - JOURNAL ARTICLE
AU  - JB Schulz
AU  - RT Matthews
AU  - BG Jenkins
AU  - RJ Ferrante
AU  - D Siwek
AU  - DR Henshaw
AU  - PB Cipolloni
AU  - P Mecocci
AU  - NW Kowall
AU  - BR Rosen
TI  - Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo
AID  - 10.1523/JNEUROSCI.15-12-08419.1995
DP  - 1995 Dec 01
TA  - The Journal of Neuroscience
PG  - 8419--8429
VI  - 15
IP  - 12
4099  - http://www.jneurosci.org/content/15/12/8419.short
4100  - http://www.jneurosci.org/content/15/12/8419.full
SO  - J. Neurosci.1995 Dec 01; 15
AB  - Nitric oxide may be a key mediator of excitotoxic neuronal injury in the central nervous system. We examined the effects of the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) on excitotoxic striatal lesions. 7-NI significantly attenuated lesions produced by intrastriatal injections of NMDA, but not kainic acid or alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 7-NI attenuated secondary striatal excitotoxic lesions produced by the succinate dehydrogenase inhibitor malonate, and the protection was reversed by L- arginine but not by D-arginine, 7-NI produced nearly complete protection against striatal lesions produced by systemic administration of 3-nitropropionic acid (3-NP), another succinate dehydrogenase inhibitor, 7-NI protected against malonate induced decreases in ATP, and increases in lactate, as assessed by 1H magnetic resonance spectroscopy. 7-NI had no effects on spontaneous electrophysiologic activity in the striatum in vivo, suggesting that its effects were not mediated by an interaction with excitatory amino acid receptors. 7-NI attenuated increases in hydroxyl radical, 8-hydroxy-2-deoxyguanosine and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. The present results implicate neuronal nitric oxide generation in the pathogenesis of both direct and secondary excitotoxic neuronal injury in vivo. As such they suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.