Selective S1PR1 Modulation Provides Protection In Intracerebral Hemorrhage

Background and purpose Inflammation contributes to perihematoma edema and exacerbates brain injury after intracerebral hemorrhage(ICH). Preclinical and clinical studies have shown that attenuated brain inflammation via sphingosine-1-phosphate receptor(S1PR) modulator fingolimod can improve clinical outcome of ICH. However, fingolimod-induced bradycardia via S1PR3 could limit its use in stroke patients. Therefore, we investigated the therapeutic efficacy of a novel selective S1PR1 modulator RP101075 in a mouse model of ICH.Methods ICH was induced by injection of autologous blood(30ul) in 332 male C57BL/6 mice. ICH mice received RP101075(n=165) or vehicle(n=167) by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurological functions, survival index until day 14, lesion volume, brain edema and immune responses were evaluated at day 1, 3 and 7 after ICH. Blood brain barrier(BBB) integrity and cell apoptosis were measured at day 3 after ICH.Results Our results show that RP101075 treatment significantly attenuated neurological deficits at all the time points tested and brain edema at day 1 and 3. It also suppressed the activation and infiltration of neutrophils, leukocytes and lymphocytes in the brain at day1 and 3. Moreover, RP101075 treatment enhanced BBB integrity and alleviated cell apoptosis at day 3 after ICH.Conclusions RP101075 provides protection in mice after ICH. The efficacy and advantageous pharmacological features of RP101075 warrant further investigations on its mechanisms of action and potential translational values for ICH patients.