Saint-Pierre Martine, Tremblay Marie-Eve, Sik Attila, Gross Robert E, Cicchetti Francesca
Centre de Recherche en Neurosciences, Sainte-Foy, Quebec, Canada.
J Neurochem. 2006 Aug;98(3):760-72. doi: 10.1111/j.1471-4159.2006.03923.x.
We investigated the effects of combined systemic exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB) in 6-month-old rats, an animal model of Parkinson's disease resulting from environmental toxin exposure. Following two doses of PQ (10 mg/kg) and MB (30 mg/kg), 52% of animals developed fatal lung injury. Examination of the remaining animals showed degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta 6 weeks, but not 4 weeks, following PQ/MB. In contrast, microglial activation was observed at 4 weeks, but had abated by 6 weeks. Compared with our previous findings in younger rats, these results suggest increased susceptibility of older animals to lung and brain toxicity from PQ/MB exposure. Microglial activation preceded, and therefore likely contributed to, DA neurodegeneration. Further, electron microscopy revealed an abnormal appearance of the Golgi apparatus at 4 weeks that was confirmed using double immunostaining for tyrosine hydroxylase and Golgi. This suggests that PQ/MB causes protein processing dysfunction in nigral DA neurons that may be either a direct effect of PQ/MB or the result of microglial activation.
我们研究了除草剂百草枯（PQ）和杀菌剂代森锰（MB）联合全身暴露对6月龄大鼠的影响，该大鼠是因环境毒素暴露导致帕金森病的动物模型。在给予两剂PQ（10毫克/千克）和MB（30毫克/千克）后，52%的动物出现致命性肺损伤。对其余动物的检查显示，在PQ/MB处理后6周而非4周，黑质致密部的多巴胺能（DA）神经元发生退化。相比之下，在4周时观察到小胶质细胞活化，但在6周时已减弱。与我们之前在幼龄大鼠中的研究结果相比，这些结果表明老年动物对PQ/MB暴露所致的肺和脑毒性更敏感。小胶质细胞活化先于DA神经变性，因此可能是其原因。此外，电子显微镜显示在4周时高尔基体外观异常，这通过酪氨酸羟化酶和高尔基体的双重免疫染色得到证实。这表明PQ/MB导致黑质DA神经元中的蛋白质加工功能障碍，这可能是PQ/MB的直接作用或小胶质细胞活化的结果。
