Mohanakumar K P, Hanbauer I, Chiueh C C
Unit on Neurotoxicity and Neuroprotection, Laboratory of Clinical Sciences, NIMH, NIH, Bethesda, MD 20892, USA.
J Chem Neuroanat. 1998 Jun;14(3-4):195-205. doi: 10.1016/s0891-0618(98)00032-5.
We investigated the effects of nitric oxide on an in vitro and in vivo generation of hydroxyl radicals, and in vivo neurotoxicity caused by intranigral infusion of ferrous citrate in rats. The formation of hydroxyl radicals in vitro, without exogenous hydrogen peroxide, was dose-dependent. Some nitric oxide donors (e.g. sodium nitroprusside) stimulated, while others (nitroglycerin, diethylamine/nitric oxide, nitric oxide in Ringer's solution) suppressed hydroxyl radical generation in vitro. A significant increase in extra-cellular hydroxyl radicals was detected in a brain microdialysis study. Intranigral infusion of ferrous citrate caused long-lasting lipid peroxidation and dopamine depletion in the ipsilateral nigral region and striatum, respectively. Sub-acute dopamine depletion in the striatum was positively correlated with acute lipid peroxidation in substantia nigra. Intranigral administration of nitric oxide did not affect striatal dopamine. Interestingly, nitric oxide in Ringer's protected nigral neurones against the oxidative injury. The results demonstrate that a regional increase in the levels of iron can result in hydroxyl radical generation and lipid peroxidation leading to neurotoxicity. It also demonstrates that exogenous nitric oxide can act as hydroxyl radical scavenger and protect neurones from oxidative injury.
我们研究了一氧化氮对体外和体内羟自由基生成的影响，以及大鼠黑质内注射柠檬酸亚铁所致的体内神经毒性。在无外源性过氧化氢的情况下，体外羟自由基的形成呈剂量依赖性。一些一氧化氮供体（如硝普钠）可刺激体外羟自由基的生成，而其他一些（硝酸甘油、二乙胺/一氧化氮、林格氏液中的一氧化氮）则抑制其生成。在一项脑微透析研究中检测到细胞外羟自由基显著增加。黑质内注射柠檬酸亚铁分别导致同侧黑质区域和纹状体持久的脂质过氧化和多巴胺耗竭。纹状体内亚急性多巴胺耗竭与黑质内急性脂质过氧化呈正相关。黑质内给予一氧化氮不影响纹状体多巴胺。有趣的是，林格氏液中的一氧化氮可保护黑质神经元免受氧化损伤。结果表明，铁水平的区域性升高可导致羟自由基生成和脂质过氧化，进而引起神经毒性。这也表明外源性一氧化氮可作为羟自由基清除剂，保护神经元免受氧化损伤。
