Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Striatal malonate lesions are attenuated in neuronal nitric oxide synthase knockout mice. 866 23

The gene defect in Huntington's disease (HD) may result in an impairment of energy metabolism. Malonate and 3-nitropropionic acid (3-NP) are inhibitors of succinate dehydrogenase that produce energy depletion and lesions that closely resemble those of HD. Oral supplementation with creatine or cyclocreatine, which are substrates for the enzyme creatine kinase, may increase phosphocreatine (PCr) or phosphocyclocreatine (PCCr) levels and ATP generation and thereby may exert neuroprotective effects. We found that oral supplementation with either creatine or cyclocreatine produced significant protection against malonate lesions, and that creatine but not cyclocreatine supplementation significantly protected against 3-NP neurotoxicity. Creatine and cyclocreatine increased brain concentrations of PCr and PCCr, respectively, and creatine protected against depletions of PCr and ATP produced by 3-NP. Creatine supplementation protected against 3-NP induced increases in striatal lactate concentrations in vivo as assessed by 1H magnetic resonance spectroscopy. Creatine and cyclocreatine protected against malonate-induced increases in the conversion of salicylate to 2,3- and 2,5-dihydroxybenzoic acid, biochemical markers of hydroxyl radical generation. Creatine administration protected against 3-NP-induced increases in 3-nitrotyrosine concentrations, a marker of peroxynitrite-mediated oxidative injury. Oral supplementation with creatine or cyclocreatine results in neuroprotective effects in vivo, which may represent a novel therapeutic strategy for HD and other neurodegenerative diseases.
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PMID:Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. 941 96