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Striatal malonate lesions are attenuated in neuronal nitric oxide synthase knockout mice
J B Schulz1, P L Huang, R T Matthews
1Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital, Boston, 02114, USA.
Abstract:
Intrastriatal administration of the reversible succinate dehydrogenase inhibitor malonate produces both energy depletion and striatal lesions by a secondary excitotoxic mechanism. To investigate the role of nitric oxide (NO.) in the pathogenesis of the lesions we examined malonate toxicity in mice in which the genes for neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide synthase (eNOS) were disrupted. Malonate striatal lesions were significantly attenuated in the nNOS mutant mice, and they were significantly increased in the eNOS mutant mice. Malonate-induced increases in levels of 2,3- and 2,5-dihydroxybenzoic acid/salicylate, markers of hydroxyl radical generation, were significantly attenuated in the nNOS knockout mice. Malonate-induced increases in 3-nitrotyrosine, a marker for peroxynitrite-mediated damage, were blocked in the nNOS mice, whereas a significant increase occurred in the eNOS mice. These findings show that NO. produced by nNOS results in generation of peroxynitrite, which plays a role in malonate neurotoxicity.
Insights
Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) contributes to malonate-induced neurotoxicity. Blocking nNOS reduces damage, while endothelial nitric oxide synthase (eNOS) appears protective against malonate excitotoxicity.
Area of Science:
- Neuroscience
- Biochemistry
- Toxicology
Background:
- Malonate, a succinate dehydrogenase inhibitor, causes energy depletion and striatal lesions via excitotoxicity.
- The precise role of nitric oxide (NO) in malonate-induced neurotoxicity remains unclear.
Purpose of the Study:
- To investigate the involvement of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) in the pathogenesis of malonate-induced striatal lesions.
Main Methods:
- Examined malonate toxicity in mice with disrupted nNOS and eNOS genes.
- Assessed striatal lesions, hydroxyl radical generation (using salicylate markers), and peroxynitrite-mediated damage (using 3-nitrotyrosine).
Main Results:
- Malonate-induced striatal lesions were reduced in nNOS mutant mice but increased in eNOS mutant mice.
- Hydroxyl radical generation was attenuated in nNOS knockout mice.
- Peroxynitrite-mediated damage was blocked in nNOS mutant mice, contrasting with an increase in eNOS mutant mice.
Conclusions:
- NO produced by nNOS plays a critical role in generating peroxynitrite, contributing to malonate neurotoxicity.
- eNOS may have a protective role against malonate excitotoxicity.