A novel probucol analogue lowers amyloid-beta level and prevents blood-brain barrier dysfunction in diabetic mice  — The Association Specialists
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A novel probucol analogue lowers amyloid-beta level and prevents blood-brain barrier dysfunction in diabetic mice  (21986)

Arazu Sharif 1 2 , Ryu Takechi 2 3 , John Mamo 2 3 4 , Virginie Lam 2 3
  1. Curtin Medical School, Curtin University, Bentley, WA, Australia
  2. Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
  3. Curtin School of Population Health, Curtin University, Perth , Western Australia, Australia
  4. Neurovascular and Metabolic Disease, Perron Institute for Neurological and Translational Science, Perth, WA, Australia

Heightened vascular exposure to elevated levels of free amyloid-beta (Aβ) and lipoprotein-Aβ contributes to blood-brain barrier (BBB) dysfunction and the development of neurodegenerative processes in the brain. Alterations in lipoprotein metabolism can affect the circulating levels of lipoprotein-Aβ by increasing its production in lipogenic organs, such as the intestine, and reducing its clearance in the blood. Therefore, BBB disruption in diabetes may result from increased capillary exposure to lipoprotein-Aβ due to disturbances in lipoprotein metabolism. Previously, probucol, a historic lipid-lowering drug, was shown to mitigate the intestinal production and secretion into blood of lipoprotein-Aβ and prevent neurovascular pathologies in murine models of dietary-induced BBB dysfunction. However, the high hydrophobicity of probucol limits its bioavailability and therapeutic potential. To address this, a novel probucol analogue has been developed by our lab. In this study, using the db/db mouse model of diabetes, we investigated whether probucol and its novel analogue, through modulation of peripheral lipoprotein-Aβ, protect BBB integrity and prevent neurovascular inflammation. Our results indicated elevated levels of enterocytic Aβ, and plasma Aβ42 and Aβ oligomers, concomitant with increased BBB permeability in control db/db mice. Both probucol and equimolar administration of the probucol analogue reduced intestinal Aβ production. However, only probucol analogue lowered plasma Aβ42 and Aβ oligomer levels and prevented BBB dysfunction, oxidative stress, and neuroinflammation. Collectively, this data suggests that the novel probucol prodrug has high potential in modulating peripheral Aβ levels and preventing BBB disturbances in diabetes.