Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin
Methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin
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DOI：
10.1111/j.1460-9568.2009.07059.x
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发表时间：
2010-01-01
影响因子：
3.4
通讯作者：
Silva, Ana P.
中科院分区：
文献类型：
--
作者：
Goncalves, Joana;Baptista, Sofia;Silva, Ana P.
甲基苯丙胺（METH）对脑细胞造成不可逆的损伤，导致神经和精神异常。然而，急性METH中毒危及生命的潜在机制仍不清楚。事实上，大多数假设集中在神经元内的事件，如多巴胺氧化，氧化应激和兴奋性毒性。然而，最近的报告表明，胶质细胞可能有助于甲基苯丙胺诱导的神经病理学。在本研究中，我们研究了急性高剂量METH（30 mg/kg;腹腔注射）诱导的海马功能障碍，重点关注炎症过程和几种神经元结构蛋白的变化。为此，在METH后的不同时间点处死3月龄雄性野生型C57 BL/6 J小鼠。我们观察到，METH引起的炎症反应，其特征在于星形胶质细胞和小胶质细胞的反应，和肿瘤坏死因子（TNF）系统的改变。事实上，胶质细胞酸性蛋白（GFAP）和CD 11b免疫反应性上调，同样TNF-α和TNF受体1蛋白水平。此外，还研究了METH对海马神经元的影响，我们观察到β III微管蛋白表达下调。为了阐明METH诱导的可能的神经元功能障碍，分析了几种神经元蛋白。Syntaxin-1、calbindin D28 k和tau蛋白水平下调，而突触素上调。我们还评估了抗炎药是否可以预防或减轻METH诱导的神经炎症，并且我们得出结论，吲哚美辛（10 mg/kg; i. p.）阻止了MET诱导的胶质细胞活化以及TNF系统和β III微管蛋白的改变。总之，我们证明了METH触发炎症过程并导致海马神经元功能障碍，这可以通过抗炎治疗来预防。
Methamphetamine (METH) causes irreversible damage to brain cells leading to neurological and psychiatric abnormalities. However, the mechanisms underlying life-threatening effects of acute METH intoxication remain unclear. Indeed, most of the hypotheses focused on intra-neuronal events, such as dopamine oxidation, oxidative stress and excitotoxicity. Yet, recent reports suggested that glia may contribute to METH-induced neuropathology. In the present study, we investigated the hippocampal dysfunction induced by an acute high dose of METH (30 mg/kg; intraperitoneal injection), focusing on the inflammatory process and changes in several neuronal structural proteins. For that, 3-month-old male wild-type C57BL/6J mice were killed at different time-points post-METH. We observed that METH caused an inflammatory response characterized by astrocytic and microglia reactivity, and tumor necrosis factor (TNF) system alterations. Indeed, glial fibrillary acidic protein (GFAP) and CD11b immunoreactivity were upregulated, likewise TNF-alpha and TNF receptor 1 protein levels. Furthermore, the effect of METH on hippocampal neurons was also investigated, and we observed a downregulation in beta III tubulin expression. To clarify the possible neuronal dysfunction induced by METH, several neuronal proteins were analysed. Syntaxin-1, calbindin D28k and tau protein levels were downregulated, whereas synaptophysin was upregulated. We also evaluated whether an anti-inflammatory drug could prevent or diminish METH-induced neuroinflammation, and we concluded that indomethacin (10 mg/kg; i.p.) prevented METH-induced glia activation and both TNF system and beta III tubulin alterations. In conclusion, we demonstrated that METH triggers an inflammatory process and leads to neuronal dysfunction in the hippocampus, which can be prevented by an anti-inflammatory treatment.