The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord
The Dual Cyclooxygenase/5-Lipoxygenase Inhibitor Licofelone Attenuates P-Glycoprotein-Mediated Drug Resistance in the Injured Spinal Cord
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DOI：
10.1089/neu.2012.2587
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发表时间：
2013-02-01
影响因子：
4.2
通讯作者：
Grill, Raymond J.
中科院分区：
文献类型：
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作者：
Dulin, Jennifer N.;Moore, Meredith L.;Grill, Raymond J.
目前还没有有效的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希望，但临床试验在很大程度上是不成功的。P-糖蛋白（Pgp，Abcb 1b）是血-脊髓屏障的药物外排转运蛋白，限制血源性外源性物质穿透脊髓。疾病如癌症中病理性Pgp上调导致对多种治疗药物的耐药性增强。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介导的药物抗性是否减少了利鲁唑向受损脊髓的递送。在雄性Sprague-Dawley大鼠T10的中度挫伤后，我们观察到Pgp表达在SCI后3天至10个月的进行性空间扩散增加。脊髓摄取的i. p. -在野生型而非Abcb 1-a敲除大鼠中，SCI后递送的利鲁唑显著减少，这突出了Pgp在SCI后介导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利可非龙促进SCI后脊髓输送利鲁唑的能力。我们发现，在脊髓损伤后72小时，利可非龙既降低了Pgp表达，又提高了利鲁唑在损伤部位的生物利用度。这项工作突出了Pgp介导的耐药性作为SCI治疗药物递送的重要障碍，并建议将利卡非龙作为一种新的组合治疗策略，以增强治疗药物向受损脊髓的递送。
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 Abcb1-aknockout 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.