Guo Xin, Wang Yue, Tao Wanying, Wu Guojun, Li Xingyue, Wang Jingxian, Zhang Shengguang, Ren Zijing, Zhou Peiyang
Department of Neurology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, 441100 Xiangyang, China.
Yangtze River Shipping General Hospital/Wuhan Brain Hospital, 430015 Wuhan, China.
Int Immunopharmacol. 2025 May 27;156:114700. doi: 10.1016/j.intimp.2025.114700. Epub 2025 Apr 21.
The regulation of sphingosine 1-phosphate receptor 5 (S1PR5) expression has been implicated in the pathogenesis of several neurological disorders. However, the role of the S1PR5 agonist A-971432 in cerebral ischemia/reperfusion (CI/R) injury remains unclear. In this study, we observed that the expression of S1PR5 elevated after middle cerebral artery occlusion (MCAO) in a mouse model. We administered S1PR5 intraperitoneally at a dose of 0.1 mg/kg for three consecutive days after MCAO to investigate the potential effects of A-971432. Our in vivo experiments revealed that A-971432 significantly mitigated neurological deficits and infarct volume, ameliorated neuronal injury in the ischemic cortex and hippocampus, and suppressed apoptosis and inflammatory responses. Mechanistically, A-971432 activated the PI3K/Akt/mTOR signaling pathway and inhibited the P38/ERK/JNK pathway, suggesting that both the PI3K/Akt and MAPK pathways are involved in the anti-inflammatory and anti-apoptotic effects of A-971432 in CI/R injury. Additionally, we constructed AAV-shRNA-S1pr5 viruses and found that silencing S1pr5 significantly exacerbated neuronal apoptosis and inflammatory responses in CI/R mice, exacerbating neurological deficits and expanding infarct volume. Based on these findings, we conclude that A-971432 mitigates CI/R injury-induced apoptosis and inflammatory responses through the PI3K/Akt and MAPK pathways, and S1PR5 can serve as a promising therapeutic target for ischemic stroke treatment.
鞘氨醇-1-磷酸受体5（S1PR5）表达的调控与多种神经系统疾病的发病机制有关。然而，S1PR5激动剂A-971432在脑缺血/再灌注（CI/R）损伤中的作用仍不清楚。在本研究中，我们观察到在小鼠大脑中动脉闭塞（MCAO）模型中，S1PR5的表达在MCAO后升高。在MCAO后，我们以0.1 mg/kg的剂量连续三天腹腔注射A-971432，以研究其潜在作用。我们的体内实验表明，A-971432显著减轻神经功能缺损和梗死体积，改善缺血皮层和海马区的神经元损伤，并抑制细胞凋亡和炎症反应。机制上，A-971432激活PI3K/Akt/mTOR信号通路并抑制P38/ERK/JNK通路，这表明PI3K/Akt和MAPK通路均参与A-971432在CI/R损伤中的抗炎和抗凋亡作用。此外，我们构建了AAV-shRNA-S1pr5病毒，发现沉默S1pr5会显著加剧CI/R小鼠的神经元凋亡和炎症反应，加重神经功能缺损并扩大梗死体积。基于这些发现，我们得出结论，A-971432通过PI3K/Akt和MAPK通路减轻CI/R损伤诱导的细胞凋亡和炎症反应，并且S1PR5可作为缺血性中风治疗的一个有前景的治疗靶点。
