title: Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage.
abstract: Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH.
  
  
  
  ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2(-/-) mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH.
  
  
  
  RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced the counts of brain-infiltrating lymphocytes, neutrophils, and microglia, as well as cytokine expression after ICH. Enhanced blood-brain barrier integrity and alleviated neuronal death were also seen in ICH mice after RP101075 treatment.
  
  
  
  S1PR1 modulation via RP101075 provides protection in experimental ICH. Together with the advantageous pharmacological features of RP101075, these results warrant further investigations of its mechanisms of action and translational values in ICH patients.
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Na
authors.initials: N
authors.lastname: Sun
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Kaibin
authors.initials: K
authors.lastname: Shi
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Kristofer
authors.initials: K
authors.lastname: Wood
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Sheth
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).
authors.forename: DeRen
authors.initials: D
authors.lastname: Huang
authors.affiliation: From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.). fshi@tmu.edu.cn.
authors.forename: Fu-Dong
authors.initials: FD
authors.lastname: Shi
mesh_terms: D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000032:analysis; D004268:DNA-Binding Proteins / Q000172:deficiency; D004353:Drug Evaluation, Preclinical; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology; D009474:Neurons / Q000473:pathology; D063065:Organophosphonates / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000037:antagonists & inhibitors; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; D000813:Anilides; D016207:Cytokines; D004268:DNA-Binding Proteins; D063065:Organophosphonates; C499308:Rag2 protein, mouse; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors
keywords: RP101075; S1PR1 modulator; immune modulation; intracerebral hemorrhage