Mechanisms of Osteopontin-Induced Stabilization of Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Rats

Abstract

Background and Purpose-Osteopontin (OPN) is an inducible, multifunctional, extracellular matrix protein that may be protective against blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). However, the protective mechanisms remain unclear. Methods-We produced the endovascular perforation model of SAH in rats and studied the time course of OPN induction in brains by Western blotting and immunofluorescence (nϭ50). Then, 34 rats were randomly assigned to sham (nϭ3), shamϩOPN small interfering RNA (siRNA, nϭ3), SAHϩnegative control siRNA (nϭ14), and SAHϩOPN siRNA (nϭ14) groups, and 109 rats were allocated to shamϩvehicle (nϭ17), shamϩrecombinant OPN (nϭ17), SAHϩvehicle (nϭ33), SAHϩrecombinant OPN (nϭ31), and SAHϩrecombinant OPNϩL-arginyl-glycyl-L-aspartate motif-containing hexapeptide (nϭ11) groups. The effects of OPN siRNA or recombinant OPN on BBB disruption and related proteins were studied. Results-OPN was significantly induced in reactive astrocytes and capillary endothelial cells, peaking at 72 hours after SAH, during the recovery phase of BBB disruption. Blockage of endogenous OPN induction exacerbated BBB disruption and was associated with a reduction of angiopoietin-1 and mitogen-activated protein kinase (MAPK) phosphatase-1 (an endogenous MAPK inhibitor), activation of MAPKs, and induction of vascular endothelial growth factor-A at 72 hours after SAH, whereas recombinant OPN treatment improved it and was associated with MAPK phosphatase-1 induction, MAPK inactivation, and vascular endothelial growth factor-A reduction, which was blocked by L-arginyl-glycyl-L-aspartate motif-containing hexapeptide at 24 hours after SAH. Vascular endothelial growth factor-B and angiopoietin-2 levels were unchanged. Conclusions-OPN

Preservation of Tropomyosin-Related Kinase B (TrkB) Signaling by Sodium Orthovanadate Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats

“…19 On the other hand, VEGF was upregulated and associated with blood-brain barrier disruption in the brain after SAH. 20 In this study, there were no significant changes in expression levels of m-BDNF, IGF-1, or VEGF after SAH. One possible reason for this discrepancy is that post-SAH brain injuries in this study were less severe and not enough for changing the expression levels of growth factors compared with the previous study.…”

“…19,20 Serum IGF-1 concentrations were reported to decrease in the acute phase of human SAH and to be a predictive factor for poor outcome. 19 On the other hand, VEGF was upregulated and associated with blood-brain barrier disruption in the brain after SAH.…”

“…One possible reason for this discrepancy is that post-SAH brain injuries in this study were less severe and not enough for changing the expression levels of growth factors compared with the previous study. 20 Preserved IGF-1 levels in SOV-treated SAH animals at 4 hours may also be explained by the fact that SOV prevented post-SAH brain injuries.…”

Role of HCN Channels in Neuronal Hyperexcitability after Subarachnoid Hemorrhage in Rats

“…All experiments were performed in accordance with China Animal Welfare Legislation and were approved by the Third Military Medical University Committee on Ethics in the Care and Use of Laboratory Animals. The endovascular perforation model of SAH was produced as reported earlier (Kusaka et al, 2004;Luo et al, 2010;Suzuki et al, 2010). Briefly, Male Sprague Dawley rats (240 -270 g) were anesthetized with sodium pentobarbital (40 mg/kg, intraperitoneal).…”

Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice

“…The time points were selected because previous studies reported that post-SAH BBB disruption peaked within 24 hours and was reversed by 48-72 hours following experimental SAH. 23,29 The brain water content was measured at 24 and 48 hours postsurgery, and BBB permeability and Western blot analyses were evaluated at 24 hours postsurgery (Fig. 1 upper).…”