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 MAPK inhibitor, SB203580 was delivered with PDGF-AA in naïve animals. Post-assessment 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 24–72 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. Interpretation PDGFR-α signaling may contribute to BBB impairment via p38 MAPK mediated 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.

Can Soy Diet be Protective in Severe and Diffuse Traumatic Brain Injury?

“…The amount of disruption of BBB was shown 71%, but soy diet prevented this disruption. The reported disruption of BBB at 48 posttrauma is in agreement with results on other studies [36,37]. The protective effect of soy on the permeability of BBB has been shown mediated to the reduction of endothelial hypoxia-inducible factor 1-alpha (HIF1α) and vascular endothelial growth factor (VEGF) [38].…”

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

“…16,22,23 However, the involvement of RAGE and its association with these pathogenic events remain unclear. The evidence shown here implicates the RAGE singling pathway in the development of EBI after ICH, thus presenting a possible therapeutic target.…”

“…Evans Blue Staining BBB permeability was evaluated using Evans blue staining at 24 and 72 hours after ICH as described by Ma et al 16 with minor modifications. The rats were anesthetized and given 2% Evans blue solution (8 mL/kg, Sigma-Aldrich) by direct injection into the femoral vein.…”

Matrix Metalloproteinase Regulation in Intracerebral Hemorrhage

“…Imatinib, a platelet-derived growth factor receptor alpha (PDGFR-a) antagonist used in the treatment of chronic lymphocytic leukemia, has been shown to inhibit MMP-9, MMP-10, and MMP-13 activity in murine models of ICH. Imatinib in an autologous blood-induced murine model showed decreased ipsilateral brain edema and improved neurobehavioral functioning, while its administration in thrombin-induced murine ICH models resulted in decreased bloodbrain barrier permeability [57] .…”