Activation of PKC Isoform β_I at the Blood–Brain Barrier Rapidly Decreases P-Glycoprotein Activity and Enhances Drug Delivery to the Brain

<jats:p> P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood–brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-α-induced reduction of P-glycoprotein activity was prevented by a PKCβ<jats:sub>I/II</jats:sub> inhibitor, LY333531, and mimicked by a PKCβ<jats:sub>I/II</jats:sub> activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCβ<jats:sub>I</jats:sub>, but not PKCβ<jats:sub>II</jats:sub>. Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [<jats:sup>3</jats:sup>H]-verapamil without compromising tight junction integrity. Thus, PKCβ<jats:sub>I</jats:sub> activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCβ<jats:sub>I</jats:sub> at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain. </jats:p>