Tu1616 Rpc1063 Is a Potent S1p1r Agonist With Efficacy in the Samp1yitfc Ileitis Model: New Evidence for Dysregulation of S1p Metabolism in Preclinical Models and Patients With Inflammatory Bowel Disease

Scott, Fiona L.; Behrens, En-hui; Clemons, Bryan; Gonzalez-Cabrera, Pedro J.; Bamias, Giorgos; Rosen, Hugh; Peach, Robert; Rivera–Nieves, Jesús

doi:10.1016/s0016-5085(13)62985-6

Cited by 1 publication

(2 citation statements)

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“…65,66 However, unlike fingolimod, RP101075 has been reported to have almost no affinity to S1PR3. 29 It has been reported that RP101075 has affinity to both S1PR1 and S1PR5 with the half maximal effective concentration (EC50) of RP101075 reported to be more than 20 times less for S1PR1 (0.27nM±0.06) than for S1PR5 (5.9nM±1.0) 67 , which indicates that RP101075 has a significantly higher affinity to S1PR1 than S1PR5. Moreover, S1PR5 is predominantly reported in the white matter tracts and oligodendrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…18,27,28 In 2016, Scott et al first identified RP101075 as a metabolite of ozanimod and reported that both ligands exhibit similar S1PR1 selectivity profiles. 29 Therefore, in the second half of this study, we utilized our in vitro primary HBMEC model to investigate the impact of RP101075 and/or ozanimod (parent compound) on endothelial cell survival following HGD and assessed the involvement of S1PR1 activation. In the brain, S1PR1expression in peripheral immune cells 30 , neurons 31 , astrocytes 32 , microglia 33 , and endothelial cells [34][35][36] has been well documented.…”

Section: Introductionmentioning

confidence: 99%

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Selective S1PR1 activation improves brain infarction, neurological outcome, and cerebrovascular endothelial health following experimental ischemic injury

Shi

Wendt

et al. 2023

Preprint

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Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in endothelial cells and receptor activation plays an important role in mediating endothelial function and health, thus showing promise as a pharmacologic target for acute ischemic stroke (AIS) treatment. Here, we examined the effect of a selective S1PR1 ligand, RP101075, on infarct volume and neurological outcome in adult male mice subjected to transient middle cerebral artery occlusion (tMCAO). Concomitantly, we examined S1PR1 expression profile in the ischemic mouse brain, as well as S1PR1 expression and impact of receptor activation on human brain microvascular endothelial cell (HBMEC) proliferation and survival following hypoxia plus glucose deprivation (HGD). We observed that RP101075 administration at onset of reperfusion reduced infarct volume and lessened neurological deficits in tMCAO mice and these responses were S1PR1 dependent. Additionally, we observed that tMCAO increased brain S1PR1 protein levels and flow cytometry revealed increases in S1PR1 levels are greatest in brain endothelial cells compared to other brain cell types (astrocyte, neuron, microglia). In cultured HBMECs, RP101075 increased cell proliferation and ozanimod, parent compound of RP1010175, increased live cell count during HGD; this response was S1PR1 dependent. In conclusion, S1PR1 activation improves neuroprotection/outcome post-stroke and preserves brain endothelial cell survival following ischemia-like injury.

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