Hermann Dirk M, Kilic Ertugrul, Spudich Annett, Krämer Stefanie D, Wunderli-Allenspach Heidi, Bassetti Claudio L
Department of Neurology, University Hospital Zurich, Switzerland.
Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Ann Neurol. 2006 Nov;60(5):489-498. doi: 10.1002/ana.21012.
The blood-brain barrier is a natural diffusion barrier, which expresses active carriers extruding drugs on their way to the brain back into the blood against concentration gradients. Whereas these so-called adenosine triphosphate-binding cassette (ABC) transporters prevent the brain entry of toxic compounds under physiological conditions, they complicate pharmacotherapies in neurological disease. Recent observations in animal models of ischemic stroke, drug-resistant epilepsy, and brain cancer showed that the prototype of ABC transporters, ABCB1, is upregulated on brain injury, deactivation of this carrier considerably enhancing the accumulation of neuroprotective, antiepileptic, and chemotherapeutic compounds. These studies provide the proof of concept that the efficacy of brain-targeting drugs may significantly be improved when drug efflux is blocked. Under clinical conditions, efforts currently are made to enhance drug accumulation by selecting new compounds that do not bind to efflux carriers or deactivating ABC transporters by targeted downregulation or pharmacological inhibition. We predict that strategies aiming at circumventing drug efflux may greatly facilitate progress in neurological therapies.
血脑屏障是一种天然的扩散屏障，它表达主动转运载体，能将药物在进入大脑的途中逆浓度梯度回输到血液中。在生理条件下，这些所谓的三磷酸腺苷结合盒（ABC）转运蛋白可阻止有毒化合物进入大脑，但它们使神经系统疾病的药物治疗变得复杂。最近在缺血性中风、耐药性癫痫和脑癌动物模型中的观察表明，ABC转运蛋白的原型ABCB1在脑损伤时会上调，抑制这种载体可显著增强神经保护、抗癫痫和化疗化合物的蓄积。这些研究提供了概念验证，即当药物外排被阻断时，脑靶向药物的疗效可能会显著提高。在临床条件下，目前正在努力通过选择不与外排载体结合的新化合物或通过靶向下调或药理抑制使ABC转运蛋白失活来增强药物蓄积。我们预测，旨在规避药物外排的策略可能会极大地促进神经治疗的进展。
