Effect of obesity on early blood–brain barrier disruption following transient focal cerebral ischemia

Abstract

Objective: We determined the effect of obesity on early post-ischemic blood–brain barrier (BBB) disruption. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) or standard chow for 16 weeks. Transient focal cerebral ischemia was induced by directly ligating the middle cerebral artery for 2 h. Early BBB disruption was assessed by measuring Evans Blue and sodium fluorescein extravasation at 3 h of reperfusion. Results: Obesity produced an increase in cerebral vasodilation/hyperaemia during reperfusion. N(omega)-propyl-L-arginine and 7-nitroindazole (neuronal nitric oxide synthase inhibitors) failed to alter the cerebral vasodilation/hyperaemia in lean mice, but significantly inhibited the cerebral vasodilation/hyperaemia in obese mice. The magnitude of early post-ischemic BBB disruption was significantly greater in obese mice compared with lean mice. Topical treatment with N(omega)-propyl-L-arginine, 7-nitroindazole or N(omega)-propyl-L-arginine, 7-nitroindazole (a non-specific nitric oxide synthase [NOS] inhibitor) completely abolished the BBB disruption in lean mice, but only partially suppressed the BBB disruption in obese mice. Furthermore, a reduced matrix metallopeptidase (MMP)-9 activity and increased endothelial NOS accompanied with unchanged protein expression of tight/adherens junctions were found in cerebral cortex of obese mice. Conclusions: Our findings suggest that obesity exacerbates early post-ischemic BBB disruption via a mechanism independent of MMP or NOS. HFD exacerbates BBB disruption at 24 h of reperfusion via MMP-9.