The activation of microglia in response to intracerebral hemorrhagic stroke is one of the principal components of the progression of this disease. It results in the formation of pro-inflammatory cytokines that lead to neuronal death, a structural deterioration that, in turn interferes with functional recovery. Metabotropic glutamate receptor 5 (mGluR5) is highly expressed in reactive microglia and is involved in the pathological processes of brain disorders, but its role in intracerebral hemorrhage (ICH) remains unknown. We hypothesized that mGluR5 regulates microglial activation and ICH maintenance. In this study, collagenase-induced ICH mice received a single intraperitoneal injection of the mGluR5 antagonist-, MTEP, or vehicle 2 h after injury. We found that acute ICH upregulated mGluR5 and microglial activation. mGluR5 was highly localized in reactive microglia in the peri-hematomal cortex and striatum on days 3 and 7 post-ICH. The MTEP-mediated pharmacological inhibition of mGluR5 in vivo resulted in the substantial attenuation of acute microglial activation and IL-6, and TNF-α release. We also showed that the blockade of mGluR5 markedly reduced cell apoptosis, and neurodegeneration and markedly elevated neuroprotection. Furthermore, the MTEP-mediated inhibition of mGluR5 significantly reduced the lesion volume and improved functional recovery. Taken together, our results demonstrate that ICH injury enhances mGluR5 expression in the acute and subacute stages and that mGluR5 is highly localized in reactive microglia. The blockade of mGluR5 reduces ICH-induced acute microglial activation, provides neuroprotection and promotes neurofunctional recovery after ICH. The inhibition of mGluR5 may be a relevant therapeutic target for intracerebral hemorrhagic stroke.

中文翻译：

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急性代谢性谷氨酸受体5的体内介导介导的急性脑出血引起的小胶质细胞活化和神经元死亡的减弱。

响应于脑出血性中风的小胶质细胞的激活是该疾病进展的主要成分之一。它会导致促炎性细胞因子的形成，从而导致神经元死亡，从而导致结构退化，进而干扰功能恢复。代谢型谷氨酸受体5（mGluR5）在反应性小胶质细胞中高度表达，并参与脑部疾病的病理过程，但其在脑出血（ICH）中的作用仍然未知。我们假设mGluR5调节小胶质细胞活化和ICH维持。在这项研究中，胶原酶诱导的ICH小鼠在受伤后2小时接受了一次腹膜内注射mGluR5拮抗剂，MTEP或媒介物。我们发现急性ICH上调了mGluR5和小胶质细胞激活。在ICH后第3天和第7天，mGluR5高度定位于血肿周围皮质和纹状体的反应性小胶质细胞中。MTEP介导的体内对mGluR5的药理抑制作用导致急性小胶质细胞活化和IL-6以及TNF-α的释放大大减弱。我们还表明，对mGluR5的阻断显着降低了细胞凋亡，并降低了神经变性并显着提高了神经保护作用。此外，MTEP介导的mGluR5抑制显着降低了病变体积并改善了功能恢复。综上所述，我们的结果表明，ICH损伤可在急性和亚急性阶段增强mGluR5的表达，而mGluR5高度位于反应性小胶质细胞中。阻断mGluR5可减少ICH诱导的急性小胶质细胞活化，ICH后提供神经保护作用并促进神经功能恢复。mGluR5的抑制可能是脑出血性中风的相关治疗靶标。