摘要
A major theory of neuronal damage in neurodegenerative diseases is that activation of excitatory amino acid receptors may play a role. In the case of neurodegenerative diseases activation of excitatory amino acid receptors may occur as a consequence of a defect in energy metabolism, which then leads to partial neuronal depolarization and activation of voltage-dependent NMDA receptors. This leads to calcium influx into the cell which is followed by activation of several deleterious processes. Amongst these are the generation of free radicals by mitochondria and the activation of nitric oxide synthase (NOS), leading to production of nitric oxide. Nitric oxide can react with Superoxide to produce peroxynitrite, which can then damage lipids, proteins and DNA. Consistent with these proposed mechanisms we found that 3-nitropropionic acid, an irreversible succinate dehydrogenase inhibitor, produces selective striatal lesions in both rats and primates by a secondary excitotoxic mechanism. This compound produces striatal lesions and delayed chorea and dystonia following accidental ingestion in mam. We found that it produces energy depletion in the striatum in vivo, and secondary excitotoxic lesions. Chronic low grade systemic administration of 3-nitropropionic acid produces striatal lesions which show age-dependence, spiny neuron dendritic changes, and selective neuronal vulnerability similar to that seen in Huntington’s disease. Administration of 3-nitropropionic acid to primates resulted in apomorphine inducible chorea. Histologic examination with GFAP and calbindin staining showed a dorsal-vental gradient of cell loss, and sparing of NADPH-diaphorase neuron. These lesions therefore closely resemble Huntington’s disease, and in primates there is an apomorphine inducible chorea. The lesions are accompanied by increased hydroxyl radical generation and they are attenu ated by both free radical spin traps and a selective inhibitor of neuronal NOS. The free radical spin traps attenuate hydroxyl radical production, yet they have no effects on striatal energy metabolism or striatal electrophysiologic activity in vivo, arguing against a direct effect on excitatory amino acid receptors. The NOS inhibitor also attenuates MPTP neurotoxicity. Free radical and NOS inhibitors may therefore be useful in the treatment of Huntington’s disease and Parkinson’s disease.
摘要译文
神经退行性疾病中神经元损伤的主要理论是兴奋性氨基酸受体的激活可能起作用。在神经退行性疾病的情况下，兴奋性氨基酸受体的激活可能由于能量代谢缺陷而发生，其然后导致部分神经元去极化和电压依赖性NMDA受体的激活。这导致钙流入细胞，随后激活几种有害过程。其中包括线粒体产生的自由基和一氧化氮合成酶（NOS）的活化，导致产生一氧化氮。一氧化氮可以与超氧化物反应生成过氧亚硝酸盐，然后可以破坏脂质，蛋白质和DNA。与这些提出的机制一致，我们发现3-硝基丙酸（一种不可逆的琥珀酸脱氢酶抑制剂）通过二级兴奋毒性机制在大鼠和灵长类动物中产生选择性纹状体损伤。该化合物在乳房中意外摄入后会产生纹状体病变和延迟的舞蹈病和肌张力障碍。我们发现它在体内纹状体和继发性兴奋毒性病变中产生能量耗尽。慢性低等级全身给予3-硝基丙酸产生纹状体病变，其表现出与亨廷顿病相似的年龄依赖性，多刺神经元树突变化和选择性神经元脆弱性。向灵长类动物施用3-硝基丙酸导致阿扑吗啡可诱导的舞蹈病。 GFAP和钙结合蛋白染色的组织学检查显示细胞丢失的背侧 - 向量梯度，以及NADPH-心肌黄酶神经元的保留。因此，这些病变与亨廷顿氏病非常相似，并且在灵长类动物中存在阿扑吗啡可诱导的舞蹈病。病变伴随着羟基自由基的产生增加，并且它们被自由基自旋陷阱和神经元NOS的选择性抑制剂所削弱。自由基自旋陷阱减弱了羟基自由基的产生，但它们对体内的纹状体能量代谢或纹状体电生理活动没有影响，反对对兴奋性氨基酸受体的直接影响。 NOS抑制剂还减弱MPTP神经毒性。因此，自由基和NOS抑制剂可用于治疗亨廷顿舞蹈病和帕金森氏病。
M. Flint Beal[1]. Bioenergetics in Oxidative Damage in Neurodegenerative Diseases. Neurodegenerative Diseases[M].DE: Springer, 1996: 171-179