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

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Abstract
Objective: Accumulated evidence suggests that the primary cause of poor outcome after subarachnoid hemorrhage is not only cerebral arterial narrowing but also early brain injury. Our objective was to determine the effect of recombinant osteopontin, a pleiotropic extracellular matrix glycoprotein, on early brain injury after subarachnoid hemorrhage in rats. Design: Controlled in vivo laboratory study. Setting: Animal research laboratory. Subjects: One hundred seventy-seven male adult Sprague-Dawley rats weighing 300 to 370 g. Interventions: The endovascular perforation model of subarachnoid hemorrhage was produced. Subarachnoid hemorrhage or sham-operated rats were treated with an equal volume (1 μL) of pre-subarachnoid hemorrhage intracerebroventricular administration of two dosages (0.02 and 0.1 μg) of recombinant osteopontin, albumin, or vehicle. Body weight, neurologic scores, brain edema, and blood–brain barrier disruption were evaluated, and Western blot analyses were performed to determine the effect of recombinant osteopontin on matrix metalloproteinase-9, substrates of matrix metalloproteinase-9 (zona occludens-1, laminin), tissue inhibitor of matrix metalloproteinase-1, inflammation (interleukin-1β), and nuclear factor-κB signaling pathways. Measurements and Main Results: Treatment with recombinant osteopontin prevented a significant loss in body weight, neurologic impairment, brain edema, and blood–brain barrier disruption after subarachnoid hemorrhage. These effects were associated with the deactivation of nuclear factor-κB activity, inhibition of matrix metalloproteinase-9 induction, the maintenance of tissue inhibitor of matrix metalloproteinase-1, the consequent preservation of the cerebral microvessel basal lamina protein laminin, and the tight junction protein zona occludens-1. Conclusions: These results demonstrate that recombinant osteopontin treatment is effective for early brain injury after subarachnoid hemorrhage.