Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity
Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity
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DOI：
10.1016/j.expneurol.2004.01.010
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发表时间：
2004-05-01
影响因子：
5.3
通讯作者：
Hastings, TG
中科院分区：
文献类型：
--
作者：
LaVoie, MJ;Card, JP;Hastings, TG
先前的研究表明，大鼠纹状体中甲基苯丙胺（甲基）诱导的对多巴胺能和血清素能轴突的毒性。尽管几项研究已经确定了该病变模型中反应性星形胶质病的性质，但尚未详细研究小胶质细胞的反应。在这项研究中，我们表征了暴露于甲基苯丙胺后，反应性小胶质细胞增多症与纹状体中多巴胺能轴突神经病理学改变的时间关系。成年雄性Sprague-Dawley大鼠接受甲基苯丙胺的神经毒性方案，并在治疗后12小时或1、2、4和6天存活。免疫组织化学方法用于评估甲基苯丙胺治疗大鼠整个大脑中小胶质细胞的反应性变化，特别关注纹状体。在所有甲基苯丙胺处理的动物的大脑中，明显的形态变化表明了反应性小胶质细胞增多症，在盐水处理的对照动物中不存在。这些包括细胞形态的增生变化，这些变化大大增加了反应性小胶质细胞的大小和染色强度。纹状体反应性小胶质细胞变化的定量分析表明，这些变化在腹外侧区域内最健壮，并且在甲基苯丙胺给药后2天是最大的。组织的分析还表明，小胶质细胞激活之前是纹状体多巴胺纤维的病理变化。反应性小胶质细胞增多症，在纹状体外区域（体感和梨状皮层以及周长灰色）中也观察到了VA。这些数据表明，小胶质细胞对甲基苯丙胺给药的响应，至少在纹状体中，小胶质细胞的一致，健壮和选择性激活，这是轴突病理学的形态指标的出现。这些观察结果增加了活化的小胶质细胞可能有助于甲基苯丙胺诱导的神经毒性的可能性。 （c）2004 Elsevier Inc.保留所有权利。
Previous studies have demonstrated methamphetamine (METH)-induced toxicity to dopaminergic and serotonergic axons in rat striatum. Although several studies have identified the nature of reactive astrogliosis in this lesion model, the response of microglia has not been examined in detail. In this investigation, we characterized the temporal relationship of reactive microgliosis to neuropathological alterations of dopaminergic axons in striatum following exposure to methamphetamine. Adult male Sprague-Dawley rats were administered a neurotoxic regimen of methamphetamine and survived 12 h, or 1, 2, 4, and 6 days after treatment. Immunohistochemical methods were used to evaluate reactive changes in microglia throughout the brain of methamphetamine-treated rats, with a particular focus upon striatum. Pronounced morphological changes, indicative of reactive microgliosis, were evident in the brains of all methamphetamine-treated animals and were absent in saline-treated control animals. These included hyperplastic changes in cell morphology that substantially increased the size and staining intensity of reactive microglia. Quantitative analysis of reactive microglial changes in striatum demonstrated that these changes were most robust within the ventrolateral region and were maximal 2 days after methamphetamine administration. Analysis of tissue also revealed that microglial activation preceded the appearance of pathological changes in striatal dopamine fibers. Reactive microgliosis,,vas also observed in extra-striatal regions (somatosensory and piriform cortices, and periaqueductal gray). These data demonstrate a consistent, robust, and selective activation of microglia in response to methamphetamine administration that, at least in striatum, precedes the appearance of morphological indicators of axon pathology. These observations raise the possibility that activated microglia may contribute to methamphetamine-induced neurotoxicity. (C) 2004 Elsevier Inc. All rights reserved.