Pei G, Ebendal T
Department of Developmental Neuroscience, Uppsala University, Sweden.
Exp Neurol. 1995 Mar;132(1):105-15. doi: 10.1016/0014-4886(95)90064-0.
The irreversible mitochondrial toxin 3-nitropropionic acid (3-NPA) is a specific inhibitor of succinate dehydrogenase. We performed stereotaxic unilateral injections of 3-NPA into the nigrostriatal dopaminergic pathway in rats in order to examine its specific effects on the dopamine system. The 3-NPA-treated rats displayed unidirectional apomorphineinduced rotations, suggesting that 3-NPA selectively damages dopaminergic neurons when injected into the nigrostriatal pathway. In situ hybridization 7 weeks postinjection indicated a decrease in tyrosine hydroxylase (TH) mRNA to 30% of the noninjected side in the substantia nigra pars compacta (P < 0.05) and decreased to 62% of the noninjected side in the ventral tegmental area (VTA) (nonsignificant) of 3-NPA-lesioned rats. The number of TH mRNA positive cells showed statistically significant decreases in substantia nigra and VTA (P < 0.001) within the lesioned side. In contrast, expression of mRNAs encoding choline acetyltransferase, p75 low-affinity NGF receptor, neurotrophin tyrosine kinase receptors Trk and TrkB, and brain-derived neurotrophic factor showed neuronal sparing in several other regions of the brain. The results suggest that the nigrostriatal dopaminergic system might be selectively vulnerable to 3-NPA and demonstrate that it is possible to employ 3-NPA in a model of partial lesion of the nigrostriatal dopaminergic system resembling early stages of Parkinson's disease.
不可逆性线粒体毒素3-硝基丙酸（3-NPA）是琥珀酸脱氢酶的特异性抑制剂。我们对大鼠黑质纹状体多巴胺能通路进行了3-NPA的立体定向单侧注射，以研究其对多巴胺系统的特异性作用。经3-NPA处理的大鼠表现出阿扑吗啡诱导的单向旋转，这表明将3-NPA注入黑质纹状体通路时，它会选择性地损害多巴胺能神经元。注射后7周的原位杂交显示，3-NPA损伤大鼠黑质致密部酪氨酸羟化酶（TH）mRNA降至未注射侧的30%（P<0.05），腹侧被盖区（VTA）降至未注射侧的62%（无统计学意义）。损伤侧黑质和VTA中TH mRNA阳性细胞数量在统计学上显著减少（P<0.001）。相比之下，在大脑的其他几个区域，编码胆碱乙酰转移酶、p75低亲和力NGF受体、神经营养酪氨酸激酶受体Trk和TrkB以及脑源性神经营养因子的mRNA表达显示神经元未受影响。结果表明，黑质纹状体多巴胺能系统可能对3-NPA具有选择性易损性，并证明在类似于帕金森病早期阶段的黑质纹状体多巴胺能系统部分损伤模型中使用3-NPA是可行的。
