Modulation of GPER1 alleviates early brain injury via inhibition of A1 reactive astrocytes activation after intracerebral hemorrhage in mice

Jianchao Mao; Yongkun Guo; Huanhuan Li; Hongfei Ge; Chao Zhang; Hua Feng; Jun Zhong; Rong Hu; Xinjun Wang

doi:10.1016/j.heliyon.2024.e26909

Modulation of GPER1 alleviates early brain injury via inhibition of A1 reactive astrocytes activation after intracerebral hemorrhage in mice

Heliyon. 2024 Feb 25;10(5):e26909. doi: 10.1016/j.heliyon.2024.e26909. eCollection 2024 Mar 15.

Authors

Jianchao Mao^{1

2}, Yongkun Guo¹, Huanhuan Li², Hongfei Ge², Chao Zhang², Hua Feng², Jun Zhong², Rong Hu², Xinjun Wang¹

Affiliations

¹ Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, China.
² Department of Neurosurgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China.

Abstract

Background: Early brain injury (EBI) caused by inflammatory responses in acute phase of Intracerebral hemorrhage (ICH) plays a vital role in the pathological progression of ICH. Increasing evidences demonstrate A1 reactive astrocytes are associated with the severity of EBI. G-protein coupled estrogen receptor 1 (GPER1) has been proved mediating the neuroprotective effects of estrogen in central nervous system (CNS) disease. However, whether GPER1 plays a protective effect on ICH and A1 reactive astrocytes activation is not well studied.

Methods: ICH model was established by infused the autologous whole blood into the right basal ganglia in wild type and GPER1 knockout mice. GPER1 specific agonist G1 and antagonist G15 were administered by intraperitoneal injection at 1 h or 0.5 h after ICH. Neurological function was detected on day 1 and day 3 by open field test and corner turn test following ICH. Besides, A1 reactive astrocytes were determined by immunofluorescence staining after ICH on day 3. To further identify the possible mechanism of GPER1 mediated neuroprotective effect, Western blot assays was performed after ICH on day 3.

Results: After ICH, G1 treatment alleviated mice neurobehavior deficits on day 1 and day 3. Meanwhile, G1 treatment also significantly reduced the GFAP positive astrocytes and the C3 positive cells after ICH. Interestingly, G15 reversed the protective effect of G1 on the neurobehavior of ICH mice. Meanwhile, the expression of GFAP⁺C3⁺ A1 reactive astrocytes were also reduced by activation of GPER1. Mechanistic studies indicated TLR4 and NF-κB mediated the neuroprotective effect of GPER1.

Conclusion: Generally, activation of GPER1 alleviated the EBI through inhibiting A1 reactive astrocytes activation via TLR4/NF-κB pathway after ICH in mice. Additionally, GPER1may be a promising target for ICH treatment.

Keywords: A1 reactive astrocyte; Early brain injury; G-protein coupled estrogen receptor 1; Intracerebral hemorrhage; Toll-like receptor 4.