Pregabalin Protects Brain Tissue from Subarachnoid Hemorrhage by Enhancing HIF-1α/eNOS Signaling and VEGF Production

Abstract

We investigated the effects of different doses of pregabalin on the pathophysiologic changes in early brain injury after subarachnoid hemorrhage (SAH) in rats. Thirty-eight Wistar albino rats were divided into 4 groups: control (n= 8), SAH (n= 10), SAH plus 30 mg/kg/day of pregabalin (n= 10), and SAH plus 60 mg/kg/day of pregabalin (n= 10). SAH was induced with 0.3 mL of autologous blood injected to the cisterna magna of rats. Pregabalin was administered intraperitoneally. Oxidative stress markers, mRNA expression of endothelial nitric oxide synthase, hypoxia-inducible factor-1α, and vascular endothelial growth factor, and histopathological changes were evaluated. Pregabalin increased mRNA expression of endothelial nitric oxide synthase, hypoxia-inducible factor-1α, and vascular endothelial growth factor in a dose-dependent manner. Significant improvement in the histopathological parameters was observed at 60 mg/kg, including a decrease in diffuse hemorrhagic areas, edema and apoptotic bodies in the associated cortical area, evident vacuolization in the hippocampal area, and apoptotic bodies. However, these improvements were not observed with the lower dose (30 mg/kg). In contrast, the antioxidant effect was greater with 30 mg/kg of pregabalin than with 60 mg/kg. Although the antioxidant effect was significant with the lower dose of pregabalin, the anti-inflammatory effects via vasodilatation were more marked with the higher dose. Significant improvements in the histopathological changes were observed with the higher dose of pregabalin. The dose-dependent effects of pregabalin on SAH should be evaluated in animal studies as a function of time and in the acute and chronic phases.