Fink S L, Ho D Y, Sapolsky R M
Department of Neuroscience, Stanford University, California 94305, USA.
Exp Neurol. 1996 Apr;138(2):298-304. doi: 10.1006/exnr.1996.0068.
3-Nitropropionic acid (3-NP) irreversibly inhibits the activity of the mitochondrial enzyme succinate dehydrogenase, leading to selective striatal lesions when administered in vivo. We studied the effects of 3-NP on dissociated cultures of neurons and glia with the following findings: (a) 3-NP killed cultured striatal neurons with a median lethal dose of 2.5 mM after 20 h of incubation in 20.0 mM glucose medium. Despite its selective toxicity in vivo, cultured striatal, hippocampal, septal, and hypothalamic neurons were similarly sensitive to 3-NP incubation. (b) 3-NP's effects were remarkably energy substrate dependent, with the median lethal dose dropping over an order of magnitude when glucose concentrations were lowered to 3.0 mM, a condition that was itself nontoxic. Cultures exposed to 3-NP had a far greater sensitivity to energy availability than those exposed to glutamate. (c) Recent work suggests that 3-NP toxicity may be partially mediated by excitotoxins. Our experiments show that neither kynurenic acid, a nonspecific glutamate receptor antagonist, nor the NMDA-receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid, either in combination or alone, reduced 3-NP toxicity in striatal cultures. However, the noncompetitive NMDA antagonist MK-801 did attenuate 3-NP toxicity.
3-硝基丙酸（3-NP）不可逆地抑制线粒体酶琥珀酸脱氢酶的活性，在体内给药时会导致选择性纹状体损伤。我们研究了3-NP对神经元和神经胶质细胞解离培养物的影响，结果如下：（a）在含有20.0 mM葡萄糖的培养基中孵育20小时后，3-NP可杀死培养的纹状体神经元，其半数致死剂量为2.5 mM。尽管3-NP在体内具有选择性毒性，但培养的纹状体、海马、隔区和下丘脑神经元对3-NP孵育的敏感性相似。（b）3-NP的作用显著依赖于能量底物，当葡萄糖浓度降至3.0 mM（此条件本身无毒）时，半数致死剂量下降了一个数量级以上。暴露于3-NP的培养物对能量可用性的敏感性远高于暴露于谷氨酸的培养物。（c）最近的研究表明，3-NP毒性可能部分由兴奋性毒素介导。我们的实验表明，非特异性谷氨酸受体拮抗剂犬尿氨酸和NMDA受体拮抗剂DL-2-氨基-7-磷酸庚酸单独或联合使用，均不能降低纹状体培养物中的3-NP毒性。然而，非竞争性NMDA拮抗剂MK-801确实减弱了3-NP毒性。
