Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China.
Front Immunol. 2022 Feb 14;13:839796. doi: 10.3389/fimmu.2022.839796. eCollection 2022.
Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high rates of mortality. In the early stages of SAH, neuroinflammation is one of the important mechanisms leading to brain injury after SAH. In various central nervous system diseases, activation of RARα receptor has been proven to demonstrate neuroprotective effects. This study aimed to investigate the anti-inflammatory effects of RARα receptor activation after SAH.
Internal carotid artery puncture method used to established SAH model in Sprague-Dawley rats. The RARα specific agonist Am80 was injected intraperitoneally 1 hour after SAH. AGN196996 (specific RARα inhibitor), Msr1 siRNA and LY294002 (PI3K-Akt inhibitor) were administered the lateral ventricle before SAH. Evaluation SAH grade, neurological function score, blood-brain barrier permeability. BV2 cells and SH-SY5Y cells were co-cultured and stimulated by oxyhemoglobin to establish an model of SAH. RT-PCR, Western blotting, and immunofluorescence staining were used to investigate pathway-related proteins, microglia activation and inflammatory response. Results: The expression of RARα, Mafb, and Msr1 increased in rat brain tissue after SAH. Activation of the RARα receptor with Am80 improved neurological deficits and attenuated brain edema, blood brain barrier permeability. Am80 increased the expression of Mafb and Msr1, and reduced neuroinflammation by enhancing the phosphorylation of Akt and by inhibiting the phosphorylation of NF-κB. AGN196996, Msr1 siRNA, and LY294002 reversed the therapeutic effects of Am80 by reducing the expression of Msr1 and the phosphorylation of Akt. model of SAH, Am80 promoted M1-to-M2 phenotypic polarization in microglia and suppressed the nuclear transcription of NF-κB.
Activation of the RARα receptor attenuated neuroinflammation by promoting M1-to-M2 phenotypic polarization in microglia and regulating the Mafb/Msr1/PI3K-Akt/NF-κB pathway. RARα might serve as a potential target for SAH therapy.
蛛网膜下腔出血（SAH）是一种具有高死亡率的危及生命的脑卒中亚型。在 SAH 的早期阶段，神经炎症是导致 SAH 后脑损伤的重要机制之一。在各种中枢神经系统疾病中，已证明激活 RARα 受体具有神经保护作用。本研究旨在探讨 SAH 后激活 RARα 受体的抗炎作用。
采用颈内动脉穿刺法建立 Sprague-Dawley 大鼠 SAH 模型。SAH 后 1 小时经腹腔注射 RARα 特异性激动剂 Am80。SAH 前向侧脑室给予 AGN196996（特异性 RARα 抑制剂）、Msr1 siRNA 和 LY294002（PI3K-Akt 抑制剂）。评估 SAH 分级、神经功能评分、血脑屏障通透性。将 BV2 细胞和 SH-SY5Y 细胞共培养并用氧合血红蛋白刺激建立 SAH 模型。采用 RT-PCR、Western blot 和免疫荧光染色法检测相关通路蛋白、小胶质细胞激活和炎症反应。
SAH 后大鼠脑组织中 RARα、Mafb 和 Msr1 的表达增加。用 Am80 激活 RARα 受体可改善神经功能缺损并减轻脑水肿和血脑屏障通透性。Am80 通过增强 Akt 的磷酸化和抑制 NF-κB 的磷酸化，增加 Mafb 和 Msr1 的表达，减少神经炎症。AGN196996、Msr1 siRNA 和 LY294002 通过降低 Msr1 的表达和 Akt 的磷酸化逆转了 Am80 的治疗作用。SAH 模型中，Am80 促进小胶质细胞 M1 向 M2 表型极化，并抑制 NF-κB 的核转录。
激活 RARα 受体通过促进小胶质细胞 M1 向 M2 表型极化和调节 Mafb/Msr1/PI3K-Akt/NF-κB 通路减轻神经炎症。RARα 可能成为 SAH 治疗的潜在靶点。
