Methyl-beta-cyclodextrin and myriocin alleviate blood-brain barrier impairment in septic rats

Abstract

In this study, the effect of targeting plasma membranes by depleting cholesterol and inhibiting sphingolipid synthesis using methyl-beta-cyclodextrin (MβCD) and myriocin, respectively, on blood-brain barrier (BBB) integrity was investigated in rats under septic conditions induced by cecal ligation and puncture (CLP). Horseradish peroxidase (HRP) and Evans blue (EB) tracers were used to assess BBB permeability. Caveolin (Cav)-1, claudin-3 and -5, and glucose transporter (Glut)-1 expression was assessed using immunofluorescence staining. In septic rats, MβCD or myriocin significantly attenuated the increased BBB permeability to both tracers. Upon MβCD administration, Cav-1 immunoreactivity decreased in the cerebral cortex; however, it increased markedly in the hippocampus in CLP-operated animals. MβCD and myriocin treatments to septic rats increased claudin-3 immunoreactivity in brain regions, and the difference reached statistical significance with the former treatment. In septic rats, claudin-5 immunoreactivity in brain regions was significantly decreased by MβCD and increased by myriocin. In CLP-operated animals, MβCD and myriocin treatments increased Glut-1 immunoreactivity in the brain regions, with the differences reaching statistical significance in the cerebral cortex and hippocampus by the former, while in only the cerebral cortex by the latter treatment. In conclusion, our results suggest that altering lipid profiles of plasma membranes by MβCD and myriocin can alleviate BBB disruption in septic conditions and, hence, may account for a novel therapeutic modality.

Keywords: Blood–brain barrier; Methyl-beta-cyclodextrin; Myriocin; Sepsis.