Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine.
Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine.
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DOI：
10.1111/j.1471-4159.2012.07864.x
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发表时间：
2012-09
影响因子：
4.7
通讯作者：
O'Callaghan JP
中科院分区：
文献类型：
--
作者：
Kelly KA;Miller DB;Bowyer JF;O'Callaghan JP
脑中促炎细胞因子和趋化因子的上调（“神经炎症”）伴随神经系统疾病和神经毒性。以前，我们记录了纹状体神经炎症反应的神经毒性剂量的甲基苯丙胺（METH），即一个与多巴胺能末梢损伤和激活的小胶质细胞和星形胶质细胞的证据。当我们使用米诺环素抑制MET诱导的神经炎症时，多巴胺能神经毒性指数不受影响，但对神经炎症的抑制不完全。在这里，我们给予经典的抗炎糖皮质激素，皮质酮（CORT），试图完全抑制METH相关的神经炎症。METH单独引起纹状体促炎性细胞因子/趋化因子mRNA的大量增加，以及随后的星形胶质细胞肥大、小胶质细胞活化和多巴胺能神经末梢损伤。用急性CORT预处理小鼠未能防止对METH的神经炎症反应。令人惊讶的是，当小鼠在饮用水中用慢性CORT预处理时，观察到对METH的增强的纹状体神经炎症反应，这种作用伴随着增强的METH诱导的星形胶质细胞增生和多巴胺能神经毒性。慢性CORT预处理也使额叶皮层和海马对METH产生神经炎症反应。由于慢性CORT的使用水平与高生理应激相关，我们的数据表明，慢性CORT治疗或持续的生理应激可能会使METH的神经炎症和神经毒性反应敏感。
Up-regulation of proinflammatory cytokines and chemokines in brain (“neuroinflammation”) accompanies neurological disease and neurotoxicity. Previously, we documented a striatal neuroinflammatory response to acute administration of a neurotoxic dose of methamphetamine (METH), i.e. one associated with evidence of dopaminergic terminal damage and activation of microglia and astroglia. When we used minocycline to suppress METH-induced neuroinflammation, indices of dopaminergic neurotoxicity were not affected, but suppression of neuroinflammation was incomplete. Here, we administered the classic anti-inflammatory glucocorticoid, corticosterone (CORT), in an attempt to completely suppress METH-related neuroinflammation. METH alone caused large increases in striatal proinflammatory cytokine/chemokine mRNA and subsequent astrocytic hypertrophy, microglial activation, and dopaminergic nerve terminal damage. Pre-treatment of mice with acute CORT failed to prevent neuroinflammatory responses to METH. Surprisingly, when mice were pre-treated with chronic CORT in the drinking water, an enhanced striatal neuroinflammatory response to METH was observed, an effect that was accompanied by enhanced METH-induced astrogliosis and dopaminergic neurotoxicity. Chronic CORT pre-treatment also sensitized frontal cortex and hippocampus to mount a neuroinflammatory response to METH. Because the levels of chronic CORT used are associated with high physiological stress, our data suggest that chronic CORT therapy or sustained physiological stress may sensitize the neuroinflammatory and neurotoxicity responses to METH.