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Activation of GPER-1 Attenuates Traumatic Brain Injury-Induced Neurological Impairments in Mice

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Abstract

This study aimed to investigate the effects of G1-activated G protein-coupled estrogen receptor 1 (GPER1) on neurological impairments and neuroinflammation in traumatic brain injury (TBI) mice. The controlled cortical impingement (CCI) method was used to establish the TBI model. The mice were subjected to ovariectomy (OVX) for two weeks prior to modeling. GPER1 agonist G1 was administered by intracerebroventricular injection. Brain tissue water content was detected by wet/dry method, and blood-brain barrier damage was detected by Evans blue extravasation. The neurological impairments in mice were evaluated by open field test, Y-maze test, nest-building test, object location memory test and novel object recognition test. Ionized calcium-binding adapter molecule 1 (Iba1) staining was used to indicate the activation of microglia. Expression of M1/M2-type microglia markers and inflammatory factors were evaluated by ELISA and qRT-PCR. The G1 administration significantly reduced cerebral edema and Evans blue extravasation at injury ipsilateral cortex and basal ganglia in TBI mice. Activation of GPER1 by G1 improved the anxiety behavior and the cognitive dysfunction of mice induced by TBI. G1 administration significantly decreased Iba1-positive staining cells and the mRNA levels of CD86, macrophage cationic peptide 1 (Mcp-1), nitric oxide synthase 2 (Nos2), interleukin 1 beta (IL-1β), and macrophage inflammatory protein-2 (MIP-2), while increased the mRNA levels of interleukin 10 (IL-10), arginase1 (Arg-1) and CD206. Activation of GPER1 through G1 administration has the potential to ameliorate cognitive dysfunction induced by TBI in mice. It may also inhibit the activation of M1 microglia in cortical tissue resulting from TBI, while promoting the activation of M2 microglia and contributing to the regulation of inflammatory responses.

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The raw data supporting the conclusions of this article will be made available on request to the corresponding author by email, as requested by our department.

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This work was supported by the National Natural Science Foundation of China (no. 81971153, no. 81200902).

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  1. Yafei Xue and Yunze Zhang contributed equally to this work.

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  1. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Baqiao District, Xi’an, 710038, Shaanxi, China

    Yafei Xue, Yunze Zhang, Yingxi Wu & Tianzhi Zhao

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Yafei Xue: Data curation, Conceptualization, Methodology, Writing- Original draft preparation, Investigation, Methodology, Writing- Original draft preparation, Writing- Reviewing and Editing. Yunze Zhang: Data curation, Validation, Writing- Original draft preparation. Yingxi Wu: Data curation, Writing- Original draft preparation. Tianzhi Zhao: Conceptualization, Writing- Original draft preparation, Supervision, Writing- Reviewing and Editing.

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Xue, Y., Zhang, Y., Wu, Y. et al. Activation of GPER-1 Attenuates Traumatic Brain Injury-Induced Neurological Impairments in Mice. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03919-w

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