Effects of methyl-beta-cyclodextrin on blood-brain barrier permeability in angiotensin II-induced hypertensive rats

Abstract

The blood-brain barrier (BBB) permeability primarily increases in cerebral venules during acute hypertension. Methyl-beta-cyclodextrin (M beta CD), a cholesterol-depleting agent, decreases the expression of caveolins disrupting caveolar structures. We aimed to determine the effects of M beta CD on the BBB permeability of angiotensin (ANG) II-induced hypertensive rats. Three minutes after M beta CD administration (5 mg/kg), acute hypertension was induced by ANG II (60 mu g/kg). Evans blue (EB) and horseradish peroxidase (HRP) tracers were used to assess BBB permeability. Immunohistochemistry for caveolin (Cav)-1 and tight junction protein claudin-5 was performed. EB dye content significantly increased in both cerebral cortices and left hippocampus in M beta CD (P < 0.05), right cerebral cortex and both hippocampi in ANG II (P < 0.05; P < 0.01), and both cerebral cortices and hippocampi in M beta CD plus ANG II groups compared with controls (P < 0.05; P < 0.01). A significant decrease in claudin-5 immunostaining intensity was observed in animals treated with M beta CD compared with controls (P < 0.05). Cav-1 immunostaining intensity increased in ANG II group (P < 0.05). Ultrastructurally, HRP reaction products were observed in endothelial cells of the microvessels in the hippocampus region in M beta CD group while the tracer was mainly localized in astrocytes and neurons in ANG II, and M beta CD plus ANG II groups. The endothelial cells of the venules in the cerebral cortex of the animals in the latter experimental groups also showed an abundance of caveolar vesicles devoid of HRP reaction products. Our results revealed that M beta CD did not provide overall protective effects on BBB integrity in acute hypertension and even led to BBB disruption in normotensive animals.