期刊
ANNALS OF NEUROLOGY
卷 70, 期 6, 页码 920-931出版社
WILEY-BLACKWELL
DOI: 10.1002/ana.22549
关键词
-
资金
- NIH [R01 NS060936-01A2, R01 NS053407-01A]
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-a), 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-a following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption. Methods: Brain injury was induced by autologous arterial blood (30 mu l) or thrombin (5U) 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 naive animals. Postassessment included neurological function tests, brain edema measurement, Evans blue extravasation, immunoprecipitation, western blot, and immunohistology assay. Results: PDGFR-alpha suppression prevented neurological deficits, brain edema, and Evans blue extravasation at 24 to 72 hours following ICH. PDGFR-alpha activation led to BBB impairment and this was reversed by SB203580 in naive mice. Thrombin inhibition suppressed PDGFR-alpha activation and exogenous PDGF-AA increased PDGFR-a activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA-neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment. Interpretation: PDGFR-alpha 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-alpha signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH. ANN NEUROL 2011; 70: 920-931
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