Neuroprotective mechanisms of A-971432: Targeting S1PR5 to modulate PI3K/Akt and MAPK pathways in cerebral ischemia/reperfusion injury

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.