Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Dr., West Virginia University Health Sciences Center, Morgantown, WV 26506, USA.
Exp Neurol. 2013 Sep;247:134-42. doi: 10.1016/j.expneurol.2013.04.009. Epub 2013 Apr 28.
Methamphetamine (METH) abuse is associated with several negative side effects including neurotoxicity in specific brain regions such as the striatum. The precise molecular mechanisms by which METH usage results in neurotoxicity remain to be fully elucidated, with recent evidence implicating the importance of microglial activation and neuroinflammation in damaged brain regions. METH interacts with sigma receptors which are found in glial cells in addition to neurons. Moreover, sigma receptor antagonists have been shown to block METH-induced neurotoxicity in rodents although the cellular mechanisms underlying their neuroprotection remain unknown. The purpose of the current study was to determine if the prototypic sigma receptor antagonist, SN79, mitigates METH-induced microglial activation and associated increases in cytokine expression in a rodent model of METH-induced neurotoxicity. METH increased striatal mRNA and protein levels of cluster of differentiation 68 (CD68), indicative of microglial activation. METH also increased ionized calcium binding adapter molecule 1 (IBA-1) protein expression, further confirming the activation of microglia. Along with microglial activation, METH increased striatal mRNA expression levels of IL-6 family pro-inflammatory cytokines, leukemia inhibitory factor (lif), oncostatin m (osm), and interleukin-6 (il-6). Pretreatment with SN79 reduced METH-induced increases in CD68 and IBA-1 expression, demonstrating its ability to prevent microglial activation. SN79 also attenuated METH-induced mRNA increases in IL-6 pro-inflammatory cytokine family members. The ability of a sigma receptor antagonist to block METH-induced microglial activation and cytokine production provides a novel mechanism through which the neurotoxic effects of METH may be mitigated.
甲基苯丙胺（METH）滥用与几种负面副作用有关，包括纹状体等特定脑区的神经毒性。METH 使用导致神经毒性的确切分子机制仍有待充分阐明，最近的证据表明小胶质细胞激活和神经炎症在受损脑区中的重要性。METH 与 sigma 受体相互作用，sigma 受体除了存在于神经元中外，还存在于神经胶质细胞中。此外，sigma 受体拮抗剂已被证明可阻止啮齿动物的 METH 诱导的神经毒性，尽管其神经保护的细胞机制尚不清楚。本研究的目的是确定原型 sigma 受体拮抗剂 SN79 是否可以减轻 METH 诱导的神经毒性啮齿动物模型中小胶质细胞的激活以及相关细胞因子表达的增加。METH 增加了纹状体中分化群 68（CD68）的 mRNA 和蛋白水平，表明小胶质细胞的激活。METH 还增加了离子钙结合衔接分子 1（IBA-1）蛋白的表达，进一步证实了小胶质细胞的激活。随着小胶质细胞的激活，METH 增加了纹状体中白细胞介素 6 家族促炎细胞因子、白血病抑制因子（lif）、肿瘤坏死因子（osm）和白细胞介素 6（il-6）的 mRNA 表达水平。SN79 预处理可降低 METH 诱导的 CD68 和 IBA-1 表达增加，表明其能够预防小胶质细胞激活。SN79 还减弱了 METH 诱导的白细胞介素 6 家族促炎细胞因子的 mRNA 增加。sigma 受体拮抗剂阻断 METH 诱导的小胶质细胞激活和细胞因子产生的能力提供了一种新的机制，通过该机制，METH 的神经毒性作用可能得到缓解。
