Blood–brain barrier breakdown and repair by Src after thrombin‐induced injury

Abstract

Objective Thrombin mediates the life-threatening cerebral edema that occurs following intracerebral hemorrhage. Therefore, we examined the mechanisms of thrombin-induced injury to the blood-brain barrier (BBB) and subsequent mechanisms of BBB repair. Methods Intracerebroventricular (i.c.v.) injection of thrombin (20 U) was used to model intraventricular hemorrhage in adult rats. Results Thrombin reduced brain microvascular endothelial cell (BMVEC) and peri-vascular astrocyte immunoreactivity –indicating either cell injury or death; and, functionally disrupted the BBB as measured by increased water content and extravasation of sodium fluorescein and Evans blue dyes 24h later. Administration of non-specific src family kinase inhibitor PP2 immediately following thrombin injections blocked brain edema and BBB disruption. At 7 to 14 days after thrombin injections newborn endothelial cells and astrocytes were observed around cerebral vessels at the time when BBB permeability and cerebral water content resolved. Delayed administration of PP2 on days 2 through 6 following thrombin injections prevented resolution of the edema and abnormal BBB permeability. Interpretation Thrombin, via its PAR receptors, is postulated to activate src kinase phosphorylation of molecules that acutely injure the BBB and produce edema. Thus, acute administration of src antagonists blocks edema. In contrast, src blockade for 2-6 days following thrombin injections is postulated to prevent resolution of edema and abnormal BBB permeability in part because src kinase proto-oncogene members stimulate proliferation of newborn BMVECs and peri-vascular astrocytes in the “neurovascular niche” that repair the damaged BBB. Thus, src kinases not only mediate acute BBB injury but also mediate chronic BBB repair after thrombin-induced injury.

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

“…121 Thus, Src kinase family members mediate acute BBB injury produced by thrombin, but also mediate chronic BBB repair. 121 Additional study of thrombin and blood products that induced BBB disruption and tissue injury after stroke may identify novel targets to reduce the effects of HT.…”

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

“…For example, inhibition of the protein kinase Src can improve the acute outcome, such as neurodegeneration and abnormal behavior, after autologous blood injection in rats (96). On the other hand, prolonged inhibition of Src in the ICH model disturbs repair processes in the neurovascular niche that forms the blood-brain barrier (97), which might worsen long-term outcome. Notably, several drugs including G-CSF (64) and statins (73) have been reported to stimulate neurogenesis in hemorrhagic brain, but contribution of neurogenesis to the effects of these drugs in improving pathological and neurological parameters is unclear at present.…”

Src Family Kinase Inhibitors and their Role in the Treatment of Traumatic Brain Injuries

“…However, several studies have also shown that SFK inhibitors may have detrimental effects on cognition with prolonged use. For example, delayed PP2 administration given on days two through six post-TBI in one study extended BBB and brain edema disruption [51].…”