title: PDGFR-α inhibition preserves blood-brain barrier after intracerebral hemorrhage.
abstract: OBJECTIVE
  Perihematomal edema results from disruption of the blood-brain barrier (BBB) by key mediators, such as thrombin, following intracerebral hemorrhage (ICH). Platelet-derived growth factor receptor alpha (PDGFR-α), a tyrosine kinase receptor, was found in previous studies to play a role in orchestrating BBB impairment. In the present study, we investigated the role of PDGFR-α following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption.
  
  
  METHODS
  Brain injury was induced by autologous arterial blood (30 μl) or thrombin (5 U) injection into mice brains. A PDGFR antagonist (Gleevec) or agonist (PDGF-AA) was administered following ICH. PDGF-AA was injected with a thrombin inhibitor, hirudin, in ICH mice. Thrombin-injected mice were given Gleevec or PDGF-AA neutralizing antibody. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, was delivered with PDGF-AA in naïve animals. Postassessment included neurological function tests, brain edema measurement, Evans blue extravasation, immunoprecipitation, western blot, and immunohistology assay.
  
  
  RESULTS
  PDGFR-α suppression prevented neurological deficits, brain edema, and Evans blue extravasation at 24 to 72 hours following ICH. PDGFR-α activation led to BBB impairment and this was reversed by SB203580 in naïve mice. Thrombin inhibition suppressed PDGFR-α activation and exogenous PDGF-AA increased PDGFR-α activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA-neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment.
  
  
  CONCLUSIONS
  PDGFR-α signaling may contribute to BBB impairment via p38 MAPK-mediated matrix metalloproteinase (MMP) activation/expression following ICH, and thrombin may be the key upstream orchestrator. The therapeutic interventions targeting the PDGFR-α signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda Medical Center, Loma Linda, CA 92354, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Ma
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.forename: Nikan
authors.initials: N
authors.lastname: Khatibi
authors.forename: William
authors.initials: W
authors.lastname: Rolland
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001479:Basal Ganglia / Q000187:drug effects; D001549:Benzamides; D001804:Blood Transfusion, Autologous / Q000009:adverse effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D001929:Brain Edema / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005070:Evans Blue; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000627:therapeutic use; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D010879:Piperazines / Q000008:administration & dosage; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000009:adverse effects; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000906:Antibodies; D001549:Benzamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D005070:Evans Blue; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D008666:Metalloendopeptidases; C093642:SB 203580