期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 30, 期 7, 页码 1373-1383出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2010.21
关键词
blood-brain barrier; CNS drugs; P-glycoprotein; PKCbeta; protein kinase C; tumor necrosis factor alpha (TNF-alpha)
资金
- National Institutes of Health, National Institute of Environmental Health Sciences
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-alpha (TNF-alpha) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-alpha-induced reduction of P-glycoprotein activity was prevented by a PKC beta(I/II) inhibitor, LY333531, and mimicked by a PKC beta(I/II) activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKC beta(I), but not PKC beta(II). Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [H-3]-verapamil without compromising tight junction integrity. Thus, PKC beta(I) activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKC beta(I) at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1373-1383; doi:10.1038/jcbfm.2010.21; published online 3 March 2010
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