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Open Access Research

Long-term probucol therapy continues to suppress markers of neurovascular inflammation in a dietary induced model of cerebral capillary dysfunction

Ryusuke Takechi, Menuka M Pallebage-Gamarallage, Virginie Lam, Corey Giles and John CL Mamo*

Author Affiliations

School of Public Health, and CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Bentley, GPO Box U1987, Perth 6845, WA, Australia

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Lipids in Health and Disease 2014, 13:91  doi:10.1186/1476-511X-13-91

Published: 3 June 2014

Abstract

Background

Probucol has been shown to prevent cerebral capillary disturbances characterized by blood-to-brain extravasation of plasma derived proteins and neurovascular inflammation in mice maintained on western-styled diets for 12 weeks. However the effect of probucol on capillary integrity in aging models with capillary dysfunction is not known.

Methods

Wild-type C57BL6 mice were randomized to a low-fat (LF); saturated-fat (SFA); or SFA + Probucol diet for up to12 months of intervention.

Results

Mice fed the LF diet had substantially greater parenchymal abundance of plasma derived IgG and apo B lipoproteins at 12 months, compared to LF mice at 3 months of intervention. Markers of neurovascular inflammation were also greater at 12 months in LF fed mice compared to LF mice at 3 months. The SFA diet exacerbated the aging induced parenchymal abundance of IgG and of apo B lipoproteins and neurovascular inflammation at 12 months. The SFA effects were associated with increased production of intestinal lipoprotein amyloid-β (Aβ). The co-provision of probucol with the SFA completely abolished heightened inflammation at 12 months. Probucol attenuated SFA-induced capillary permeability but had only a modest inhibitory effect on parenchymal retention of apoB lipoproteins. The improvements in markers of inflammation and capillary integrity because of probucol correlated with enterocytic genesis of chylomicron Aβ.

Conclusion

In this long-term feeding study, probucol profoundly suppressed dietary SFA induced disturbances in capillary integrity but had a more modest effect on age-associated changes.

Keywords:
Brain capillaries; Amyloid-β; Apolipoprotein B; Blood–brain barrier; Enterocytes; Neuroinflammation; Probucol; Saturated fatty acids