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Activating PKC-ß1 at the blood-brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS
Wang, X., Hawkins, B., & Miller, D. S. (2011). Activating PKC-ß1 at the blood-brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS. Journal of Cerebral Blood Flow and Metabolism, 31(6), 1371-1375. https://doi.org/10.1038/jcbfm.2011.44
Upregulation of blood–brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-b1 (PKC-b1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-b1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-b1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries and reversed the effect of dioxin on brain uptake of verapamil in dioxin-dosed rats. Thus, targeting BBB PKC-b1 may be an effective strategy to improve drug delivery to the brain, even in drug-resistant individuals