title: Inhibition of P-glycoprotein function by procyanidine on blood-brain barrier.
abstract: The inhibitory effects of procyanidine, one of the components from the bark of Pinus massoniana Lamb, on the P-glycoprotein (P-gp) function of the blood-brain barrier (BBB) were studied using in vitro rat brain microvessel endothelial cells (RBMECs) and nude mice transplanted with human cerebroma. Quantitative accumulation and efflux of rhodamine 123 (Rh123), a P-gp substrate, were determined using a fluorescence spectrophotometer as a measure of P-gp function. Procyanidine markedly increased the accumulation of Rh123 by inhibiting its efflux in a dose-dependent manner. A 5-fold increase in cellular Rh123 was observed for procyanidine at 10 micromol/L. The verapamil-stimulated ATPase activity in plasma membrane vesicles from the RBMECs was estimated by measuring inorganic phosphate liberation. Procyanidine significantly inhibited the verapamil-induced P-gp ATPase activity by 78% when pretreated with 10 micromol/L in a concentration-dependent manner. The inhibition of P-gp by procyanidine was suggested to be at least partly due to its inhibition of P-gp ATPase. Procyanidine markedly improved the therapeutic effects of adriamycin (ADM) on nude mice transplanted with human cerebroma, compared with solitary treatment of ADM. The combination of 80 mg/kg procyanidine with 2 mg/kg ADM significantly elevated the days of survival with an increase in life span of 76%. The findings suggested that procyanidine was a potent inhibitor of P-gp on BBB and could improve the therapeutic effects on cerebral tumors of some drugs which are difficult to accumulate in the brain.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. heling92@hotmail.com
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.forename: Chuan
authors.initials: C
authors.lastname: Zhao
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Lu-Yong
authors.initials: LY
authors.lastname: Zhang
authors.forename: Yuan-Zheng
authors.initials: YZ
authors.lastname: Xia
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002392:Catechin / Q000494:pharmacology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000378:metabolism; D028223:Pinus / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology*; D044945:Proanthocyanidins / Q000494:pharmacology*; D051381:Rats; D020112:Rhodamine 123 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044946:Biflavonoids; D010936:Plant Extracts; D044945:Proanthocyanidins; D020112:Rhodamine 123; C017674:procyanidin; D002392:Catechin; D014700:Verapamil; D000251:Adenosine Triphosphatases