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PDGFR-? inhibition preserves blood-brain barrier after intracerebral hemorrhage.

ABSTRACT: 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 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-? following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption.Brain injury was induced by autologous arterial blood (30 ?l) 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.PDGFR-? suppression prevented neurological deficits, brain edema, and Evans blue extravasation at 24 to 72 hours following ICH. PDGFR-? activation led to BBB impairment and this was reversed by SB203580 in naïve mice. Thrombin inhibition suppressed PDGFR-? activation and exogenous PDGF-AA increased PDGFR-? activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA-neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment.PDGFR-? 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-? signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH.

SUBMITTER: Ma Q

PROVIDER: S-EPMC3405848 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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PDGFR-α inhibition preserves blood-brain barrier after intracerebral hemorrhage.

Ma Qingyi Q Huang Bin B Khatibi Nikan N Rolland William W Suzuki Hidenori H Zhang John H JH Tang Jiping J

Annals of neurology 20111201 6

<h4>Objective</h4>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.<h4>Me ...[more]

PMID: 22190365

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Project description:Blood-brain barrier (BBB) disruption and subsequent brain edema play important roles in the secondary neuronal death and neurological dysfunction that are observed following intracerebral hemorrhage (ICH). In previous studies, transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanosensitive channel, was shown to induce cytotoxicity in many types of cells and to play a role in orchestrating barrier functions. In the present study, we explored the role of TRPV4 in ICH-induced brain injury, specifically investigating its effect on BBB disruption. Autologous arterial blood was injected into the basal ganglia of rats to mimic ICH. Adult male Sprague Dawley rats were randomly assigned to sham and experimental groups for studies on the time course of TRPV4 expression after ICH. The selective TRPV4 antagonist HC-067047 and TRPV4 siRNA were administered to evaluate the effects of TRPV4 inhibition. GSK1016790A, a TRPV4 agonist, was administered to naive rats to verify the involvement of TRPV4-induced BBB disruption. A PKC inhibitor, dihydrochloride (H7), and a selective RhoA inhibitor, C3 transferase, were administered to clarify the involvement of the PKCα/RhoA/MLC2 pathway following ICH. Post-ICH assessments including functional tests, brain edema measurements, Evans blue extravasation, western blotting and immunohistochemical assays were performed. TRPV4 inhibition remarkably ameliorated neurological symptoms, brain edema, and neuronal death, as well as BBB disruption, 24-72 h following ICH. Meanwhile, TRPV4 blockade preserved the expression of adherens and tight junction proteins, as well as BBB integrity, by inhibiting stress fiber formation, which might be correlated with the regulation of components of the PKCα/RhoA/MLC2 pathway. Furthermore, adherens and tight junction protein degradation induced by GSK1016790A treatment in naive rats was also related to PKCα/RhoA/MLC2-pathway-mediated stress fiber formation. Based on these findings, therapeutic interventions targeting TRPV4 may represent a novel approach to ameliorate secondary brain injury following ICH.

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PDGFR-? inhibition preserves blood-brain barrier after intracerebral hemorrhage.

Publications

PDGFR-α inhibition preserves blood-brain barrier after intracerebral hemorrhage.

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