Modulation of P-glycoprotein at the blood-brain barrier: Opportunities to improve central nervous system pharmacotherapy

被引:286
作者
Miller, David S. [1 ]
Bauer, Bjoern [1 ,2 ]
Hartz, Anika M. S. [1 ,3 ]
机构
[1] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA
[2] Univ Minnesota, Coll Pharm, Duluth, MN 55812 USA
[3] Univ Minnesota, Sch Med, Duluth, MN 55812 USA
关键词
D O I
10.1124/pr.107.07109
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin ( ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.
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收藏
页码:196 / 209
页数:14
相关论文
共 121 条
[61]  
Kemper EM, 2003, CLIN CANCER RES, V9, P2849
[62]   Newly synthesized canalicular ABC transporters are directly targeted from the Golgi to the hepatocyte apical domain in rat liver [J].
Kipp, H ;
Arias, IM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (21) :15917-15925
[63]   Trafficking of canalicular ABC transporters in hepatocytes [J].
Kipp, H ;
Arias, IM .
ANNUAL REVIEW OF PHYSIOLOGY, 2002, 64 :595-608
[64]   Transporters on demand - Intrahepatic pools of canalicular ATP binding cassette transporters in rat liver [J].
Kipp, H ;
Pichetshote, N ;
Arias, IM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (10) :7218-7224
[65]   An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway [J].
Kliewer, SA ;
Moore, JT ;
Wade, L ;
Staudinger, JL ;
Watson, MA ;
Jones, SA ;
McKee, DD ;
Oliver, BB ;
Willson, TM ;
Zetterström, RH ;
Perlmann, T ;
Lehmann, JM .
CELL, 1998, 92 (01) :73-82
[66]   MDR1-P-glycoprotein (ABCB1) mediates transport of Alzheimer's amyloid-β peptides -: Implications for the mechanisms of Aβ clearance at the blood-brain barrier [J].
Kuhnke, Diana ;
Jedlitschky, Gabriele ;
Grube, Markus ;
Krohn, Markus ;
Jucker, Mathias ;
Mosyagin, Igor ;
Cascorbi, Ingolf ;
Walker, Lary C. ;
Kroemer, Heyo K. ;
Warzok, Rolf W. ;
Vogelgesang, Silke .
BRAIN PATHOLOGY, 2007, 17 (04) :347-353
[67]   Transvascular delivery of small interfering RNA to the central nervous system [J].
Kumar, Priti ;
Wu, Haoquan ;
McBride, Jodi L. ;
Jung, Kyeong-Eun ;
Kim, Moon Hee ;
Davidson, Beverly L. ;
Lee, Sang Kyung ;
Shankar, Premlata ;
Manjunath, N. .
NATURE, 2007, 448 (7149) :39-43
[68]   Transcriptional regulators of the human multidrug resistance 1 gene: recent views [J].
Labialle, S ;
Gayet, L ;
Marthinet, E ;
Rigal, D ;
Baggetto, LG .
BIOCHEMICAL PHARMACOLOGY, 2002, 64 (5-6) :943-948
[69]   New invMED1 element cis-activates human multidrug-related MDR1 and MVP genes, involving the LRP130 protein [J].
Labialle, S ;
Dayan, G ;
Gayet, L ;
Rigal, D ;
Gambrelle, J ;
Baggetto, LG .
NUCLEIC ACIDS RESEARCH, 2004, 32 (13) :3864-3876
[70]   β-Amyloid efflux mediated by p-glycoprotein [J].
Lam, FC ;
Liu, RH ;
Lu, PH ;
Shapiro, AB ;
Renoir, JM ;
Sharom, FJ ;
Reiner, PB .
JOURNAL OF NEUROCHEMISTRY, 2001, 76 (04) :1121-1128