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GPR18 Agonist Resolvin D2 Reduces Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage by Multiple Protective Mechanisms

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Abstract

Early brain injury (EBI) is the early phase of secondary complications arising from subarachnoid hemorrhage (SAH). G protein-coupled receptor 18 (GPR18) can exert neuroprotective effects during ischemia. In this study, we investigated the roles of GPR18 in different brain regions during EBI using a GPR18 agonist, resolvin D2 (RvD2). Location and dynamics of GPR18 expression were assessed by immunohistochemistry and western blotting in a rat model of SAH based on endovascular perforation. RvD2 was given intranasally at 1 h after SAH, and SAH grade, brain water content and behavior were assayed before sacrifice. TUNEL and dihydroethidium staining of the cortex were performed at 24 h after SAH. Selected brain regions were also examined for pathway related proteins using immunofluorescence and Western blotting. We found that GPR18 was expressed in meninges, hypothalamus, cortex and white matter before EBI. After SAH, GPR18 expression was increased in meninges and hypothalamus but decreased in cortex and white matter. RvD2 improved neurological scores and brain edema after SAH. RvD2 attenuated mast cell degranulation and reduced expression of chymase and tryptase expression in the meninges. In the hypothalamus, RvD2 attenuated inflammation, increased expression of proopiomelanocortin and interleukin-10, as well as decreased expression of nerve peptide Y and tumor necrosis factor-α. In cortex, RvD2 alleviated oxidative stress and apoptosis, and protected the blood–brain barrier. RvD2 also ameliorated white matter injury by elevating myelin basic protein and suppressing amyloid precursor protein. Our results suggest that GPR18 may help protect multiple brain regions during EBI, particularly in the cortex and hypothalamus. Upregulating GPR18 by RvD2 may improve neurological functions in different brain regions via multiple mechanisms.

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Funding

This research was supported by grants from the China Postdoctoral Science Foundation to TY Zhang (2019TQ0216 and 2019M660716), the Beijing Postdoctoral Science Foundation to TY Zhang (2020-ZZ-020), the National Natural Science Foundation of China to Dr. TY Zhang (82001324). And the Jiangsu Provincial Health and Family Planning Commission of China to G Zuo (QNRC2016263, H201654, and GSWS2019080).

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  1. Tongyu Zhang and Gang Zuo have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun St., Beijing, 100053, China

    Tongyu Zhang & Hongqi Zhang

  2. Department of Neurosurgery, The Affiliated Taicang Hospital, Soochow University, Taicang, Suzhou, 215400, Jiangsu, China

    Gang Zuo

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  1. Tongyu Zhang
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  2. Gang Zuo
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Contributions

TZh designed the study, performed the experiments and wrote the manuscript. GZ contributed to data analysis. HZh contributed to research design. All authors analyzed the results and approved the final version of the manuscript.

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Correspondence to Hongqi Zhang.

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The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article.

Research Involving Human and Animal Participants

All animal procedures were conducted in accordance with the ethical standards of our institution and with national regulations.

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The original online version of this article was revised: Figure 8 has been corrected.

Supplementary Information

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10571_2021_1114_MOESM1_ESM.tif

Supplementary file1 Fig. SI Photographs of representative preparations of four brain regions, for subsequent analysis by Western blot (TIF 1232 kb)

10571_2021_1114_MOESM2_ESM.tif

Supplementary file2 Fig. SII Colocalization of GPR18 (green) with markers (red) of (A-B) mast cells (chymase, tryptase) or (C) microglia (Iba1). Colocalization was not observed with microglia. The results shown are representative of those obtained with three animals from each group. Scale bars = 50 µm (TIF 2437 kb)

10571_2021_1114_MOESM3_ESM.tif

Supplementary file3 Fig. SIII RvD2 improved neurological scores of SAH rats. (A) Modified Garcia and (B) beam balance scores. Bars represent mean ± SD (n = 6 from each group). # P < 0.05 vs. Sham + vehicle group; * P < 0.05 vs. SAH + vehicle group (TIF 937 kb)

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Zhang, T., Zuo, G. & Zhang, H. GPR18 Agonist Resolvin D2 Reduces Early Brain Injury in a Rat Model of Subarachnoid Hemorrhage by Multiple Protective Mechanisms. Cell Mol Neurobiol 42, 2379–2392 (2022). https://doi.org/10.1007/s10571-021-01114-2

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