The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat.
Oxaliplatin is a novel chemotherapeutic agent which is effective against advanced colorectal cancer, but at the same time causes severe neuropathy in the peripheral nerve fibres, affecting mainly the voltage-gated sodium (Na(+)) channels (VGNaCs), according to literature. In this study the effects of oxaliplatin on the peripheral myelinated nerve fibres (PMNFs) were investigated in vitro using the isolated sciatic nerve of the adult rat. The advantage of this nerve-preparation was that stable in amplitude evoked compound action potentials (CAP) were recorded for over 1000min. Incubation of the sciatic nerve fibres in 25, 100 and 500microM oxaliplatin, for 300-700min caused dramatic distortion of the waveform of the CAP, namely broadening the repolarization phase, repetitive firing and afterhyperpolarization (AHP), related to the malfunction of voltage-gated potassium (K(+)) channels (VGKCs). At a concentration of 5microM, oxaliplatin caused broadening of the repolarization phase of the CAP only, while the no observed effect concentration was estimated to be 1microM. These findings are indicative of severe effects of oxaliplatin on the VGKCs. In contrast, the amplitude and the rise-time of the depolarization of the CAP did not change significantly, a clear indication that the VGNaCs of the particular nerve preparation were not affected by oxaliplatin. The effects of oxaliplatin on the PMNFs were similar to those of 4-aminopyridine (4-AP), a classical antagonist of VGKCs. These similarities in the pattern of action between oxaliplatin and 4-AP combined with the fact that the effects of oxaliplatin were more pronounced and developed at lower concentrations suggest that oxaliplatin acts as a potent VGKCs antagonist.
Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54 124, Greece.
Alexia
A
Kagiava
Anastasia
A
Tsingotjidou
Christos
C
Emmanouilides
George
G
Theophilidis
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055592:Biophysical Phenomena; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects*; D066298:In Vitro Techniques; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects*; D019789:Tetraethylammonium / Q000494:pharmacology
C481395:4-aminopiperidine; D000779:Anesthetics, Local; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010880:Piperidines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D000077150:Oxaliplatin; D019789:Tetraethylammonium; D008012:Lidocaine