血脑屏障上ABC转运体与中枢神经系统疾病相关性的研究进展

摘要/Abstract

摘要： ABC转运体作为血脑屏障上一类重要的外排转运体,介导了内源性物质、药物及环境毒素的外排过程。疾病状态下,ABC转运体的功能及表达会发生改变,有些疾病会导致转运体过表达或者活性增强,引发耐药现象;还有一些疾病会引起转运体损伤,导致毒素蓄积脑内,加剧疾病的发展。将各种脑部疾病与ABC转运体之间的关系研究清楚,将有助于阐明致病机制,并可为改善脑部耐药及治疗中枢神经疾病提供思路和策略。本文就这一问题,综述了血脑屏障ABC转运体在多种疾病状态下功能与表达的变化,及这些改变对疾病产生的影响,并初步探讨了相关机制,提出了一些改善耐药和治疗疾病的策略。

关键词: 中枢神经系统疾病, 血脑屏障, ABC转运体, 耐药

Abstract: ATP-binding cassette (ABC) transporters are an important type of transporters on the blood-brain barrier, which mediate the efflux of numerous endogenous substances, drugs and neurotoxicants from the brain parenchyma. Various diseases can change the expression and activity of ABC transporters. Up-regulation of ABC transporter expression and activity is a major factor to cause drug resistance in centre nervous system (CNS), while reduction of transporter expression and activity increases the accumulation of neurotoxicants in brain to aggravate the disease. Thus, elucidating the relationship between transporters and CNS diseases is critical for discovering pathogenic mechanism and providing the strategies for improving the therapeutic effects of CNS drugs. This review covers the alterations of ABC transporter expression and activity in CNS diseases, the effects of these changes on CNS diseases and the related signaling mechanisms. Finally, we also propose some strategies for improving neuroprotection and enhancing therapeutic drug delivery to the brain.

Key words: Central nervous disease, Blood-brain barrier, ATP-binding cassette transporters, Drug resistance

中图分类号:

R741

牛芳, 周芳, 吴晓兰, 王广基. 血脑屏障上ABC转运体与中枢神经系统疾病相关性的研究进展[J]. 中国临床药理学与治疗学, 2012, 17(2): 225-233.

NIU Fang, ZHOU Fang, WU Xiao-lan, WANG Guang-ji. Relationship between ABC transporters on the blood-brain barrier and central nervous diseases[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(2): 225-233.

参考文献

[1] Robey RW, Massey PR, Amiri-Kordestani L, et al. ABC transporters: unvalidated therapeutic targets in cancer and the CNS[J]. Anticancer Agents Med Chem, 2010, 10 (8): 625-633.
[2] Kemper EM, van Zandbergen AE, Cleypool C, et al. Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein[J]. Clin Cancer Res 2003, 9 (7): 2849-2855.
[3] 马德选,徐如祥. MDR1基因与脑胶质瘤[J]. 中国临床药理学与治疗学, 2001, 6 (2): 187-189.
[4] W.Henson J, Cordon-Cardo C, B.Posner J. P-glycoprotein expression in brain tumors [J]. J Neuro-Oncol, 1992, 14 (1): 37-43.
[5] Lockman PR, Mittapalli RK, Taskar KS, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer[J]. Clin Cancer Res, 2010, 16 (23): 5664-5678.
[6] Abe T, Hasegawa S, Taniguchi K, et al. Possible involvement of multidrug-resistance-associated protein (MRP) gene expression in spontaneous drug resistance to vincristine, etoposide and adriamycin in human glioma cells[J]. Int J Cancer, 1994, 58 (6): 860-864.
[7] Jin Y, Bin Z, Qiang H, et al. ABCG2 is related with the grade of glioma and resistance to mitoxantone, a chemotherapeutic drug for glioma[J]. J Cancer Res Clin, 2009, 135 (10): 1369-1376.
[8] Aronica E, Gorter JA, Redeker S, et al. Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain[J]. Epilepsia, 2005, 46 (6): 849-857.
[9] Kubota H, Ishihara H, Langmann T, et al. Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis[J]. Epilepsy Res, 2006, 68 (3): 213-228.
[10] Bauer B, Hartz AM, Pekcec A, et al. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling[J]. Mol Pharmacol, 2008, 73 (5): 1444-1453.
[11] Loscher W. Drug transporters in the epileptic brain[J]. Epilepsia, 2007, 48(Suppl 1):8-13.
[12] Bartels AL, Willemsen AT, Kortekaas R, et al. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA[J]. J Neural Transm, 2008, 115 (7): 1001-1009.
[13] Brenn A, Grube M, Peters M, et al. Beta-Amyloid downregulates MDR1-P-glycoprotein (Abcb1) expression at the blood-brain barrier in mice[J]. Int J Alzheimers Dis, 2011, 2011:1-6.
[14] Hartz AM, Miller DS, Bauer B. Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer's disease[J]. Mol Pharmacol, 2010, 77 (5): 715-723.
[15] Camus M, Deloménie C, Didier N, et al. Increased expression of MDR1 mRNAs and P-glycoprotein in placentas from HIV-1 infected women[J]. Placenta, 27 (6/7): 699-706.
[16] Zastre JA, Chan GN, Ronaldson PT, et al. Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line[J]. J Neurosci Res, 2009, 87 (4): 1023-1036.
[17] Hayashi K, Pu H, Tian J, et al. HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells[J]. J Neurochem, 2005, 93 (5): 1231-1241.
[18] Hayashi K, Pu H, Andras IE, et al. HIV-Tat protein upregulates expression of multidrug resistance protein 1 in the blood-brain barrier[J]. J Cereb Blood Flow Metab, 2006, 26 (8): 1052-1065.
[19] Tishler DM, Weinberg KI, Hinton DR, et al. MDR1 gene expression in brain of patients with medically intractable epilepsy[J]. Epilepsia, 1995, 36 (1): 1-6.
[20] Loscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters[J]. Nat Rev Neurosci, 2005, 6 (8): 591-602.
[21] Dericioglu N, Babaoglu MO, Yasar U, et al. Multidrug resistance in patients undergoing resective epilepsy surgery is not associated with C3435T polymorphism in the ABCB1 (MDR1) gene[J]. Epilepsy Res, 2008, 80 (1): 42-46.
[22] Kwan P, Baum L, Wong V, et al. Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese[J]. Epilepsy Behav, 2007, 11 (1): 112-117.
[23] Desai BS, Monahan AJ, Carvey PM, et al. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy[J]. Cell Transplant, 2007, 16 (3): 285-299.
[24] Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier[J]. Stroke, 2004, 35 (11 Suppl 1): 2628-2631.
[25] Lam FC, Liu R, Lu P, et al. β-Amyloid efflux mediated by p-glycoprotein[J]. J Neurochem, 2001, 76 (4): 1121-1128.
[26] Vogelgesang S, Cascorbi I, Schroeder E, et al. Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans[J]. Pharmacogenetics, 2002, 12 (7): 535-541.
[27] Owen A, Chandler B, Back DJ. The implications of P-glycoprotein in HIV: friend or foe[J] ？ Fundam Clin Pharmacol, 2005, 19 (3): 283-296.
[28] Zhong Y, Hennig B, Toborek M. Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells[J]. J Cereb Blood Flow Metab, 2010, 30 (3): 522-533.
[29] Yamauchi A, Dohgu S, Takata F. Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice[J]. Life Sci, 2011, 88(11/12): 529-534.
[30] Wijnholds J, deLange EC, Scheffer GL, et al. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier[J]. J Clin Invest, 2000, 105 (3): 279-285.
[31] Suzuki T, Oshimi M, Tomono K, et al. Investigation of transport mechanism of pentazocine across the blood-brain barrier using the in situ rat brain perfusion technique[J]. J Pharm Sci, 2002, 91 (11): 2346-2353.
[32] Giessmann T, May K, Modess C, et al. Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans[J]. Clin Pharmacol Ther, 2004, 76 (3): 192-200.
[33] Muller MB, Keck ME, Binder EB, et al. ABCB1 (MDR1)-type P-glycoproteins at the blood-brain barrier modulate the activity of the Hypothalamic-Pituitary-Adrenocortical system: implications for affective disorder[J]. Neuropsychopharmacology, 2003, 28 (11): 1991-1999.
[34] Köhle C, Bock KW. Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor[J]. Biochem Pharmacol, 2009, 77 (4): 689-699.
[35] Pascussi JM, Gerbal-Chaloin S, Duret C, et al. The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences[J]. Annu Rev Pharmacol Toxicol, 2008, 48:1-32.
[36] Ekins S, Erickson JA. A pharmacophore for human Pregnane X Receptor ligands[J]. Drug Metab Dispos, 2002, 30 (1): 96-99.
[37] Bauer B, Yang X, Hartz AM, et al. In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation[J]. Mol Pharmacol, 2006, 70 (4): 1212-1219.
[38] Loeb MB, Molloy DW, Smieja M, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease[J]. J Am Geriatr Soc, 2004, 52 (3): 381-387.
[39] Bauer B, Hartz AM, Miller DS. Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier[J]. Mol Pharmacol, 2007, 71 (3): 667-675.
[40] Poller B, Drewe J, Krahenbuhl S, et al. Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier[J]. Cell Mol Neurobiol, 2010, 30 (1): 63-70.
[41] Rigor RR, Hawkins BT, Miller DS. Activation of PKC isoform beta(I) at the blood-brain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain[J]. J Cereb Blood Flow Metab, 2010, 30 (7): 1373-1383.
[42] Hawkins BT, Sykes DB, Miller DS. Rapid, reversible modulation of blood-brain barrier P-glycoprotein transport activity by vascular endothelial growth factor[J]. J Neurosci, 2010, 30 (4): 1417-1425.
[43] McEwen BS, Alves SE. Estrogen actions in the Central Nervous System[J]. Endocr Rev, 1999, 20 (3): 279-307.
[44] Baldereschi M, Di Carlo A, Lepore V, et al. Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging[J]. Neurology, 1998, 50 (4): 996-1002.
[45] Nilsen J, Chen S, Irwin RW, et al. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function[J]. BMC Neurosci, 2006, 7: 74.
[46] Veliskova J. The role of estrogens in seizures and epilepsy: The bad guys or the good guys [J] ? Neuroscience, 2006, 138 (3): 837-844.
[47] Morale MC, Serra PA, L'Episcopo F, et al. Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: Glia dictates resistance versus vulnerability to neurodegeneration[J]. Neuroscience, 2006, 138 (3): 869-878.
[48] Hartz AM, Madole EK, Miller DS, et al. Estrogen receptor beta signaling through phosphatase and tensin homolog/phosphoinositide 3-kinase/Akt/glycogen synthase kinase 3 down-regulates blood-brain barrier breast cancer resistance protein[J]. J Pharmacol Exp Ther, 2010, 334 (2): 467-476.