Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat
Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat
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DOI：
10.1089/neu.2010.1723
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发表时间：
2011-09-01
影响因子：
4.2
通讯作者：
Chesselet, Marie-Francoise
中科院分区：
文献类型：
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作者：
Hutson, Che Brown;Lazo, Carlos R.;Chesselet, Marie-Francoise
帕金森病（PD）是一种神经退行性疾病，其特征是黑质纹状体多巴胺能神经元的丧失和α -突触核蛋白的积累。创伤性脑损伤（TBI）和农药都是PD的危险因素，但在实验模型中，TBI是否会导致黑质纹状体多巴胺能细胞丢失以及是否与农药协同作用尚不清楚。我们研究了创伤性脑损伤和暴露于低剂量农药百草枯（单独或联合）对成年雄性大鼠黑质纹状体多巴胺能神经元的急性和长期影响。在一项急性研究中，大鼠遭受中度脑外伤（LFP），在LFP后3和6天分别注射生理盐水或百草枯（10 mg/kg IP）， 5天后处死，进行脑免疫组织化学处理。创伤性脑损伤单独增加了黑质小胶质细胞的激活，并导致同侧多巴胺能神经元损失15%。百草枯增加了脑外伤的影响，导致双侧多巴胺能神经元损失30%，纹状体酪氨酸羟化酶（TH）免疫反应性比单独脑外伤更低，并诱导黑质致密部α -突触核蛋白积累。在长期研究中，大鼠接受中度LFP，在伤后21周和22周注射生理盐水或百草枯，4周后处死。损伤后26周，TBI单独引起30%双侧多巴胺能神经元损失，百草枯未加重。这些数据表明，脑外伤足以诱导黑质纹状体多巴胺能神经元进行性变性。此外，创伤性脑损伤和农药暴露，如果在规定的时间内发生，可能会增加帕金森病的风险。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons and the accumulation of alpha-synuclein. Both traumatic brain injury (TBI) and pesticides are risk factors for PD, but whether TBI causes nigrostriatal dopaminergic cell loss in experimental models and whether it acts synergistically with pesticides is unknown. We have examined the acute and long-term effects of TBI and exposure to low doses of the pesticide paraquat, separately and in combination, on nigrostriatal dopaminergic neurons in adult male rats. In an acute study, rats received moderate TBI by lateral fluid percussion (LFP) injury, were injected with saline or paraquat (10 mg/kg IP) 3 and 6 days after LFP, were sacrificed 5 days later, and their brains processed for immunohistochemistry. TBI alone increased microglial activation in the substantia nigra, and caused a 15% loss of dopaminergic neurons ipsilaterally. Paraquat increased the TBI effect, causing a 30% bilateral loss of dopaminergic neurons, reduced striatal tyrosine hydroxylase (TH) immunoreactivity more than TBI alone, and induced alpha-synuclein accumulation in the substantia nigra pars compacta. In a long-term study, rats received moderate LFP, were injected with saline or paraquat at 21 and 22 weeks post-injury, and were sacrificed 4 weeks later. At 26 weeks post injury, TBI alone induced a 30% bilateral loss of dopaminergic neurons that was not exacerbated by paraquat. These data suggest that TBI is sufficient to induce a progressive degeneration of nigrostriatal dopaminergic neurons. Furthermore, TBI and pesticide exposure, when occurring within a defined time frame, could combine to increase the PD risk.