Impaired cerebral microcirculation after subarachnoid hemorrhage (SAH) has been shown to be related to delayed ischemic neurological deficits (DIND). We previously demonstrated the involvement of the receptor for advanced glycation end products (RAGE) in the pathogenesis of SAH related neuronal death. In the present study, we aimed to investigate the therapeutic effects of a recombinant soluble form of RAGE (sRAGE) on microcirculation impairment following SAH. Intrathecal injection of autologous blood in rats, mixed primary astrocyte and microglia cultures exposed to hemolysates and endothelial cells ​(ECs) from human brain microvascular exposed to glia-conditioned medium or SAH patient's CSF were used as experimental SAH models in and in . The results indicated that intrathecal administration of recombinant sRAGE significantly ameliorated the vasoconstriction of cortical arterioles and associated perfusion impairment, brain edema, reduced cell death, endothelial dysfunction, and improved motor performance at 24 and 48 ​h after SAH induction in rats. The in vitro results further showed that recombinant sRAGE significantly reduced astrocyte swelling and microglia activation, in parallel with decreased mRNA expression levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-1β (IL-1β) in . Moreover, the in vitro model of SAH-induced p-eNOS and eNOS suppression, along with stress fiber formation in brain microvascular ECs, was effectively reversed by sRAGE treatment and led to a decrease in cleaved-caspase 3 expression. In summary, recombinant sRAGE effectively lessened microcirculation impairment and vascular injury after SAH via the mechanism of anti-inflammation, which may provide a potential therapeutic strategy for SAH.

中文翻译：

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重组可溶性晚期糖基化终末产物受体可改善蛛网膜下腔出血后的微循环障碍和神经炎症

蛛网膜下腔出血（SAH）后脑微循环受损已被证明与迟发性缺血性神经功能缺损（DIND）有关。我们之前证明了晚期糖基化终末产物受体（RAGE）参与 SAH 相关神经元死亡的发病机制。在本研究中，我们旨在研究重组可溶性 RAGE (sRAGE) 对 SAH 后微循环障碍的治疗效果。大鼠鞘内注射自体血液、暴露于溶血产物的混合原代星形胶质细胞和小胶质细胞培养物以及暴露于神经胶质条件培养基的人脑微血管的内皮细胞（EC）或SAH患者的CSF被用作实验性SAH模型。结果表明，鞘内注射重组 sRAGE 可显着改善皮质小动脉的血管收缩和相关的灌注损伤、脑水肿、减少细胞死亡、内皮功能障碍，并改善大鼠 SAH 诱导后 24 和 48 小时的运动表现。体外结果进一步表明，重组 sRAGE 显着减少星形胶质细胞肿胀和小胶质细胞活化，同时降低促炎细胞因子的 mRNA 表达水平，包括白介素 6 (IL-6) 和白细胞介素 1β (IL-1β)。此外，SAH 诱导的 p-eNOS 和 eNOS 抑制的体外模型，以及脑微血管 EC 中应力纤维的形成，可通过 sRAGE 治疗有效逆转，并导致 cleaved-caspase 3 表达减少。综上所述，重组sRAGE通过抗炎机制有效减轻SAH后的微循环障碍和血管损伤，这可能为SAH提供潜在的治疗策略。