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Attenuation of Acute Intracerebral Hemorrhage-Induced Microglial Activation and Neuronal Death Mediated by the Blockade of Metabotropic Glutamate Receptor 5 In Vivo

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Abstract

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.

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Acknowledgements

This work supported by the Grant from the National Natural Science Foundation of China (Approval No. 81371348). We want to thank Junzhou Zhao, Shengfeng Ji, and Yingfei Liu for their excellent support during the experiment.

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Authors and Affiliations

  1. Institute of Neurobiology, Xi’an Jiaotong University Health Science Center, 76 West Yanta Road, Xi’an, 710061, Shaanxi, People’s Republic of China

    Md Saidur Rahman, Yan Luan, Jianshui Zhang, Haixia Lu, Xinlin Chen & Yong Liu

  2. Department of Anatomy and Histology, Patuakhali Science and Technology University, Dhaka, Bangladesh

    Md Saidur Rahman

  3. Department of Neurology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China

    Jianbo Yang

  4. Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, 710038, Shaanxi, People’s Republic of China

    Zhengguo Qiu

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  1. Md Saidur Rahman
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Rahman, M.S., Yang, J., Luan, Y. et al. Attenuation of Acute Intracerebral Hemorrhage-Induced Microglial Activation and Neuronal Death Mediated by the Blockade of Metabotropic Glutamate Receptor 5 In Vivo. Neurochem Res 45, 1230–1243 (2020). https://doi.org/10.1007/s11064-020-03006-1

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