Arterial
ischemic stroke is common in neonates-1 per 2,300-5,000 births-and therapeutic targets remain insufficiently defined.
Sphingosine-1-phosphate receptor 2 (S1PR2), a major regulator of the CNS and immune systems, is injurious in adult
stroke. Here, we assessed whether S1PR2 contributes to
stroke induced by 3 h transient
middle cerebral artery occlusion (tMCAO) in S1PR2 heterozygous (HET), knockout (KO), and wild type (WT) postnatal day 9 pups. HET and WT of both sexes displayed functional deficits in Open Field test whereas injured KO at 24 h reperfusion performed similarly to naives. S1PR2 deficiency protected neurons, attenuated infiltration of inflammatory monocytes, and altered vessel-microglia interactions without reducing increased
cytokine levels in injured regions at 72 h. Pharmacologic inhibition of S1PR2 after tMCAO by
JTE-013 attenuated injury 72 h after tMCAO. Importantly, the lack of S1PR2 alleviated anxiety and brain
atrophy during chronic injury. Altogether, we identify S1PR2 as a potential new target for mitigating neonatal
stroke.