Schulz J B, Huang P L, Matthews R T, Passov D, Fishman M C, Beal M F
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital, Boston, 02114, USA.
J Neurochem. 1996 Jul;67(1):430-3. doi: 10.1046/j.1471-4159.1996.67010430.x.
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.
纹状体内注射可逆性琥珀酸脱氢酶抑制剂丙二酸，通过继发性兴奋性毒性机制导致能量耗竭和纹状体损伤。为了研究一氧化氮（NO.）在这些损伤发病机制中的作用，我们检测了神经元型一氧化氮合酶（nNOS）或内皮型一氧化氮合酶（eNOS）基因被破坏的小鼠中丙二酸的毒性。在nNOS突变小鼠中，丙二酸引起的纹状体损伤明显减轻，而在eNOS突变小鼠中则明显加重。丙二酸诱导的羟自由基生成标志物2,3-二羟基苯甲酸/水杨酸和2,5-二羟基苯甲酸/水杨酸水平的升高，在nNOS基因敲除小鼠中明显减轻。丙二酸诱导的过氧亚硝酸盐介导损伤标志物3-硝基酪氨酸的升高，在nNOS小鼠中被阻断，而在eNOS小鼠中则显著增加。这些发现表明，nNOS产生的NO.导致过氧亚硝酸盐的生成，而过氧亚硝酸盐在丙二酸神经毒性中起作用。
