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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... Abstract 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, 99mTc‐sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (×3 and ×35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (×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 ×1.7), mrp1 gene in the PNS (×1.7), and transporter activity in both the CNS and the PNS (×4 and ×8, respectively). This transporter induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Peripheral Nervous System Wiley

Patterns of P‐glycoprotein activity in the nervous system during vincristine‐induced neuropathy in rats

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References (54)

Publisher
Wiley
Copyright
Copyright © 2005 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1085-9489
eISSN
1529-8027
DOI
10.1111/j.1085-9489.2005.10308.x
pmid
16221289
Publisher site
See Article on Publisher Site

Abstract

Abstract 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, 99mTc‐sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (×3 and ×35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (×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 ×1.7), mrp1 gene in the PNS (×1.7), and transporter activity in both the CNS and the PNS (×4 and ×8, respectively). This transporter induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain.

Journal

Journal of the Peripheral Nervous SystemWiley

Published: Sep 1, 2005

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