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.

早期脑损伤 (EBI) 是蛛网膜下腔出血 (SAH) 引起的继发性并发症的早期阶段。G 蛋白偶联受体 18 (GPR18) 可在缺血期间发挥神经保护作用。在这项研究中，我们使用 GPR18 激动剂 resolvin D2 (RvD2) 研究了 GPR18 在 EBI 期间在不同大脑区域中的作用。在基于血管内穿孔的 SAH 大鼠模型中，通过免疫组织化学和蛋白质印迹评估 GPR18 表达的位置和动态。RvD2在SAH后1小时鼻内给药，处死前测定SAH分级、脑含水量和行为。在 SAH 后 24 小时进行皮质的 TUNEL 和二氢乙锭染色。还使用免疫荧光和蛋白质印迹检查了选定的大脑区域的通路相关蛋白。我们发现 GPR18 在 EBI 之前在脑膜、下丘脑、皮层和白质中表达。SAH 后，GPR18 在脑膜和下丘脑中的表达增加，但在皮层和白质中的表达减少。RvD2 改善了 SAH 后的神经系统评分和脑水肿。RvD2 减弱肥大细胞脱粒并减少脑膜中糜蛋白酶和类胰蛋白酶的表达。在下丘脑，RvD2 减轻炎症，增加阿片黑皮质素原和白细胞介素 10 的表达，以及降低神经肽 Y 和肿瘤坏死因子-α 的表达。在皮质中，RvD2 可减轻氧化应激和细胞凋亡，并保护血脑屏障。RvD2 还通过提高髓鞘碱性蛋白和抑制淀粉样前体蛋白来改善白质损伤。我们的研究结果表明，GPR18 可能有助于在 EBI 期间保护多个大脑区域，特别是在皮层和下丘脑。通过 RvD2 上调 GPR18 可能通过多种机制改善不同大脑区域的神经功能。