SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation.
SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation.
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SN79是一种Sigma受体拮抗剂，通过阻断OSMR/GP130信号传导和STAT3磷酸化，减弱了甲基苯丙胺诱导的星形胶质细胞增多症。
DOI：
10.1016/j.expneurol.2014.01.020
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发表时间：
2014-04
影响因子：
5.3
通讯作者：
Matsumoto, Rae R.
中科院分区：
文献类型：
--
作者：
Robson, Matthew J.;Turner, Ryan C.;Naser, Zachary J.;McCurdy, Christopher R.;O'Callaghan, James P.;Huber, Jason D.;Matsumoto, Rae R.
甲基苯丙胺（METH）暴露导致大脑纹状体区域的多巴胺能神经毒性，这种作用与帕金森病风险增加有关。神经炎症的各个方面，包括星形胶质细胞增生，被认为是METH神经毒性的促成因素。METH在生理相关浓度下与σ受体相互作用，并且用σ受体拮抗剂治疗已显示在啮齿动物模型中减轻METH诱导的神经毒性。然而，这些化合物是否改变中枢神经系统内神经胶质细胞对METH的反应还有待确定。因此，本研究的目的是确定σ受体拮抗剂SN 79是否减轻MET诱导的纹状体反应性星形胶质细胞增生。用METH神经毒性方案处理的雄性瑞士韦伯斯特小鼠表现出纹状体gfap mRNA的时间依赖性增加和GFAP蛋白的伴随增加，指示星形胶质细胞增生。这是第一份报告，类似于其他神经毒物，通过刺激由神经炎症引起的gp-130-连接的细胞因子信号传导激活JAK 2/STAT 3信号传导诱导星形胶质细胞增生，METH治疗也增加了星形胶质细胞制瘤素m受体（OSMR）的表达和STAT 3（Tyr-705）的磷酸化。用SN 79预处理阻断了纹状体内OSMR、STAT 3磷酸化和星形胶质细胞活化的MET诱导的增加。此外，METH处理导致纹状体细胞变性，如通过Fluoro-Jade B测量的，这种作用被SN 79减轻。目前的研究提供的证据表明，σ受体拮抗剂通过一种被认为是由各种神经毒物共享的途径来减弱MET诱导的星形胶质细胞活化。
Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.
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DOI：
10.1126/science.1166127
发表时间：
2009-02-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fontanilla D;Johannessen M;Hajipour AR;Cozzi NV;Jackson MB;Ruoho AE
通讯作者：
Ruoho AE
影响因子：
4.7
作者：
Kaushal, Nidhi;Seminerio, Michael J.;Shaikh, Jamaluddin;Medina, Mark A.;Mesangeau, Christophe;Wilson, Lisa L.;McCurdy, Christopher R.;Matsumoto, Rae R.
通讯作者：
Matsumoto, Rae R.
影响因子：
2.1
作者：
Ajmo, Craig T., Jr.;Vernon, Dionne O. L.;Cuevas, Javier
通讯作者：
Cuevas, Javier
影响因子：
5.3
作者：
Kaushal N;Matsumoto RR
通讯作者：
Matsumoto RR
影响因子：
4.2
作者：
Anderson, KJ;Fugaccia, I;Scheff, SW
通讯作者：
Scheff, SW