Mechanisms of Brain Edema Formation in Mouse Models of Intracerebral Hemorrhage

Perihematomal edema causes major neurologic deterioration following intracerebral hemorrhage (ICH), mainly resulting from the disruption of the blood-brain barrier (BBB) by multiple mediators, including inflammatory mediators and thrombin. The objective of our study was to investigate the mechanisms by which inflammation and thrombin respectively lead to the formation of brain edema following ICH. Our long-term goal is to develop new therapeutic strategies against ICH-induced brain edema by targeting: (1) VAP-1 mediated inflammatory response and (2) PDGFR-α orchestrated BBB impairment. Vascular adhesion protein-1 (VAP-1) was previously shown to promote leukocyte adhesion and transmigration. Additionally, PDGFR-α was also found to play a role in orchestrating BBB impairment. ICH injury was induced by collagenase-injection (cICH) or autologous arterial blood-injection (bICH) in mice. Two VAP-1 inhibitors, LJP1586 and semicarbazide (SCZ) were administered one hour after cICH. For mechanistic studies, VAP-1 siRNA and human recombinant VAP-1 protein were administered intracerebroventricularly. The data showed that VAP-1 inhibition reduced brain edema and neurobehavioral deficits at 24 and 72 hours after ICH induction. These two compounds were also found to decrease other adhesion molecules and cytokines expression, neutrophils infiltration and microglia/macrophage activation. The effect of VAP-1 siRNA was consistent with that of pharmacological inhibitions, whereas human recombinant VAP-1 protein abolished the protective effect of VAP-1 inhibition. The anti-inflammatory effects of VAP-1 were also corroborated using blood-induced ICH. We then proceeded to elucidate the role of PDGFR-α inhibitor-induced neuroprotection in ICH. In our ICH model, we found that PDGFR-α and its endogenous agonist PDGFAA, were upregulated in response to bICH-induced brain injury. The results showed that suppression of PDGFR-α preserved BBB integrity following bICH while activation of PDGFR-α led to BBB impairment. A p38 inhibitor reversed the effect PDGFR-α activation in naïve animals. PDGFR-α activation was suppressed by thrombin inhibition and exogenous PDGF-AA administration increased PDGFR-α activation, regardless of thrombin inhibition. In our thrombin injection model, animals receiving the treatment of a PDGF-AA neutralizing antibody or Gleevec, a PDGFR-α antagonist, showed minimized thrombin-induced BBB impairment. We concluded that anti-inflammation by targeting VAP-1 or BBB preservation by targeting PDGFR-α may serve as new treatments against brain edema following ICH.