title: Receptor for advanced glycation end-product antagonist reduces blood-brain barrier damage after intracerebral hemorrhage.
abstract: OBJECTIVE
  To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1).
  
  
  METHODS
  Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood-brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection.
  
  
  RESULTS
  Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood-brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood-brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl2-induced RAGE and nuclear factor-κB p65 upregulation.
  
  
  CONCLUSIONS
  RAGE signaling is involved in blood-brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH.
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.).
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.).
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.).
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.).
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.).
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.).
authors.forename: Liang
authors.initials: L
authors.lastname: Tan
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.). fenghua8888@aliyun.com.cn huangqingyuan@tmmu.edu.cn.
authors.forename: Qing-Yuan
authors.initials: QY
authors.lastname: Huang
authors.affiliation: From the Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine (F.Y., Q.-Y.H.), Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital (Z.W., X.L., L.T., H.F.), Third Military Medical University, Chongqing, China; and Department of Physiology and Pharmacology, Loma Linda University School of Medicine, CA (J.H.Z., J.T.). fenghua8888@aliyun.com.cn huangqingyuan@tmmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology*; D001834:Body Water / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D056324:Diffusion Tensor Imaging; D005786:Gene Expression Regulation / Q000187:drug effects; D020300:Intracranial Hemorrhages / Q000188:drug therapy* / Q000473:pathology* / Q000523:psychology; D008297:Male; D009412:Nerve Fibers / Q000473:pathology; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*
chemical_list: D001549:Benzamides; D016207:Cytokines; C572629:FPS-ZM1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: FPS-ZM1; advanced glycosylation end-product receptor; brain edema; cerebral hemorrhage; inflammation