RP001 hydrochloride improves neurological outcome after subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) results in neurological damage, acute cardiac damage and has a high mortality rate. Immunoresponse in the acute phase after SAH plays a key role in mediating vasospasm, edema, inflammation and neuronal damage. The S1P/S1PR pathway impacts multiple cellular functions, exerts anti-inflammatory and anti-apoptotic effects, promotes remyelination, and improves outcome in several central nervous system (CNS) diseases. RP001 hydrochloride is a novel S1PR agonist, which sequesters lymphocytes within their secondary tissues and prevents infiltration of immune cells into the CNS thereby reducing immune response. In this study, we investigated whether RP001 attenuates neuronal injury after SAH by reducing inflammation. S1PRs, specifically S1PR_{1, 3} not only exerts anti-inflammatory effects, but also decreases heart rate and induces atrioventricular conduction abnormalities. Therefore, we also tested whether RP001 treatment of SAH regulates cardiac functional outcome. Male adult C57BL/6 mice were subjected to SAH, and neurological function tests, echocardiography, and immunohistochemical analysis were performed. SAH induces neurological deficits and acute cardiac dysfunction compared to sham control mice. Treatment of SAH with a low-dose of RP001 induces better neurological outcome and cardiac function compared to a high-dose of RP001. Low-dose-RP001 treatment significantly decreases apoptosis, white matter damage, blood brain barrier permeability, microglial/astrocyte activation, macrophage chemokine protein-1, matrix metalloproteinase-9 and NADPH oxidase-2 expression in the brain compared to SAH control mice. Our findings indicate that low-dose of RP001 alleviates neurological damage after SAH, in part by decreasing neuroinflammation.