Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats*

Abstract

Objective-Accumulated evidence suggests that the primary cause of poor outcome after subarachnoid hemorrhage (SAH) is not only cerebral arterial narrowing, but also early brain injury (EBI). Our objective was to determine the effect of recombinant osteopontin (r-OPN), a pleiotropic extracellular matrix glycoprotein, on post-SAH EBI in rats. Design-Controlled in vivo laboratory study. Setting-Animal research laboratory.Subjects-One hundred seventy-seven male adult Sprague-Dawley rats, 300-370g.Interventions-The endovascular perforation model of SAH was produced. SAH or shamoperated rats were treated with an equal volume (1μL) of pre-SAH intracerebroventricular administration of two dosages (0.02 and 0.1μg) of r-OPN, albumin or vehicle. Body weight, neurological scores, brain edema and blood-brain barrier (BBB) disruption were evaluated, and Western blot analyses were performed to determine the effect of r-OPN on matrix metalloproteinase (MMP)-9, substrates of MMP-9 (zona occludens [ZO]-1, laminin), tissue inhibitor of MMP (TIMP)-1, inflammation (interleukin-1β), and nuclear factor (NF)-κ B signaling pathways. Measurements and MainResults-Treatment with r-OPN prevented a significant loss in body weight, neurological impairment, brain edema, and BBB disruption after SAH. These effects were associated with the deactivation of NF-κB activity, inhibition of MMP-9 induction, the maintenance of TIMP-1, and the consequent preservation of the cerebral microvessel basal lamina protein laminin, and the tight junction protein ZO-1.Conclusions-These results demonstrate that r-OPN treatment is effective for post-SAH EBI. Aneurysmal subarachnoid hemorrhage (SAH) is a common and devastating neurological disorder (1). Cerebral vasospasm has been believed to be a leading cause of mortality and morbidity (2). Recent randomized clinical trials, however, showed that clazosentan significantly reduced angiographic vasospasm but failed to improve long-term neurological outcome (3,4). This means that the treatment efforts targeting only angiographic vasospasm might not be enough to achieve a better outcome. Thus, new research efforts have focused on clarifying the pathophysiology of early brain injury (EBI) following SAH, and on developing protective strategies against it (5).Osteopontin (OPN) is a secreted extracellular matrix (ECM) glycoprotein that is involved in both physiological and pathological processes in a wide range of tissue (6). The biological functions of OPN are highly variable, and often seemingly contradictory depending on the biological scenario surrounding its induction (7). However, there is compelling evidence that OPN can, in a variety of situations, help cells survive an otherwise lethal insult (8). For example, endogenous OPN induction has consistently been found to have protective effects on ischemic injuries involving the brain and other organs (9,10). Moreover, the administration of recombinant OPN (r-OPN) markedly reduced the infarct size via anti-apoptotic actions in a transient focal cerebral ischemi...

Osteopontin Enhances Endogenous Repair After Neonatal Hypoxic–Ischemic Brain Injury

“…The latter hypothesis is in agreement with the literature because OPN has been shown to have neuroprotective effects by reducing neuronal ischemic cell death after adult stroke. 22,23 In summary, our data indicate that OPN may contribute to repair processes after neonatal HI brain injury by influencing proliferation/survival of newly formed cells. Moreover, we show here that OPN may contribute to regulation of the differentiation of newly formed cells into oligodendrocytes.…”

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

“…11 Briefly, the left common carotid artery was exposed and 4-0 sharpened nylon sutures were advanced to the left internal carotid artery until resistance was felt and perforated at the place. Immediately after surgery, saline, 3 mg/kg or 10 mg/kg of SOV was injected intraperitoneally.…”

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

“…7 Inflammatory cytokines and other factors can regulate the transcription of MMP-9 following SAH. 20,28 TNC was also reported to upregulate MMP-9 expression in cultured cancer cells. 12,14 In addition, TNKO mice showed a marked decrease in expressions of inflammatory cytokines and MMP-9 after hepatic ischemia and reperfusion.…”

“…7,11,22,23,28 MMP-9 levels in CSF and peripheral blood were significantly increased in patients with SAH. 11,22 MMP-9 degrades the extracellular matrix proteins of cerebral microvessel basal lamina and interendothelial tight junction proteins such as ZO-1, causing BBB disruption and brain edema formation.…”

“…11,22 MMP-9 degrades the extracellular matrix proteins of cerebral microvessel basal lamina and interendothelial tight junction proteins such as ZO-1, causing BBB disruption and brain edema formation. 23,28 A recent study showed that MMP-9 knockout inhibited post-SAH brain edema formation in mice. 7 Inflammatory cytokines and other factors can regulate the transcription of MMP-9 following SAH.…”