Department of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
J Neurotrauma. 2013 Feb 1;30(3):211-26. doi: 10.1089/neu.2012.2587. Epub 2013 Jan 23.
There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male Sprague-Dawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord.
目前，没有经过证实的有效治疗方法可以改善脊髓损伤 (SCI) 患者的功能恢复。许多治疗化合物在临床前研究中显示出前景，但临床试验大多不成功。P-糖蛋白 (Pgp，Abcb1b) 是血脊髓屏障的药物外排转运体，限制了血液源性外源性物质向脊髓的渗透。在癌症等疾病中病理性 Pgp 上调会导致对各种治疗药物的耐药性增加。重要的是，已经评估用于治疗 SCI 的几种药物，如利鲁唑，是 Pgp 的已知底物。因此，我们研究了 Pgp 介导的药物耐药性是否会降低利鲁唑向损伤脊髓的传递。在雄性 Sprague-Dawley 大鼠 T10 中度挫伤损伤后，我们观察到 Pgp 表达从损伤后 3 天到 10 个月逐渐增加，呈空间扩散。SCI 后，野生型大鼠腹腔给予利鲁唑的脊髓摄取明显减少，但 Abcb1a 敲除大鼠则没有，这突出了 Pgp 在介导 SCI 后药物耐药性中的关键作用。由于炎症可以驱动 Pgp 上调，我们评估了新一代双重抗炎药物 licofelone 在 SCI 后促进利鲁唑向脊髓传递的能力。我们发现 licofelone 可降低 Pgp 表达，并在 SCI 后 72 小时内增强病变部位利鲁唑的生物利用度。这项工作强调了 Pgp 介导的药物耐药性是治疗性药物输送治疗 SCI 的一个重要障碍，并表明 licofelone 是增强治疗性药物向损伤脊髓传递的一种新的组合治疗策略。
