Patterns of P-glycoprotein activity in the nervous system during vincristine-induced neuropathy in rats
Patterns of P-glycoprotein activity in the nervous system during vincristine-induced neuropathy in rats
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DOI：
10.1111/j.1085-9489.2005.10308.x
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发表时间：
2005-09-01
影响因子：
3.8
通讯作者：
Coudore, F
中科院分区：
文献类型：
--
作者：
Balayssac, D;Cayre, A;Coudore, F
长春新碱（VCT）是一种神经毒性药物，也是多药耐药（MDR）转运蛋白如P-糖蛋白（P-gp）和MDR相关蛋白1和2（MRP 1和MRP 2）的底物。这些蛋白质在中枢和外周神经系统（CNS和PNS）中表达，通常保护这些结构免受VCT的有害影响。本研究的目的是阐明MDR转运体与VCT神经毒性之间的矛盾关系。采用经验证的大鼠VCT诱导的神经病变模型，（1）通过定量实时聚合酶链反应评估CNS和PNS中mdr 1a（P-gp）、mdr 1b（P-gp）、mrp 1（MRP 1）和mrp 2（MRP 2）基因的表达，（2）使用放射性示踪剂Tc-99 m-sestamibi监测转运蛋白活性。结果显示，在对照组和治疗组动物中，mdr 1a和mdr 1b基因（分别为x3和x35）在脑中的表达高于脊神经节。CNS中的转运蛋白活性高于PNS中的转运蛋白活性（x 10）。因此，P-gp的保护可能低于PNS在CNS中，这可能是负责P-gp底物的外周神经毒性。VCT治疗增加了CNS和PNS中mdr 1a基因的表达（均为x1.7），PNS中mrp 1基因的表达（x1.7），以及CNS和PNS中转运蛋白的活性（分别为x4和x8）。这个传送器当施用镇痛药物以治疗神经性疼痛时，诱导可能引起副作用。
Vincristine (VCT) is a neurotoxic agent and also a substrate of multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and MDR-associated proteins 1 and 2 (MRP1 and MRP2). These proteins are expressed in the central and peripheral nervous systems (CNS and PNS) and normally protect these structures against the harmful effects of VCT. The aim of this study was to elucidate the paradoxical relation between the MDR transporters and the VCT neurotoxicity. With a validated rat model of VCT-induced neuropathy, (1) the expressions of mdr1a (P-gp), mdr1b (P-gp), mrp1 (MRP1), and mrp2 (MRP2) genes were assessed by quantitative real-time polymerase chain reaction, and (2) the transporter activity was monitored using a radioactive tracer, Tc-99m-sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (x3 and x35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (x 10) in the CNS than in the PNS. Hence, P-gp protection may be lower in the PNS than in the CNS, and this may be responsible for the peripheral neurotoxicity of P-gp substrates. VCT treatment increased expression of the mdr1a gene in the CNS and PNS (both x 1.7), mrp1 gene in the PNS (x1.7), and transporter activity in both the CNS and the PNS (x4 and x8, respectively). This transporter. induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain.