Oxaliplatin, an anticancer agent that affects both Na+ and K+ channels in frog peripheral myelinated axons.
The use of oxaliplatin, a relatively new chemotherapeutic agent, is somewhat limited since it produces a specific peripheral neuropathy regarding other neurotoxic anticancer platinum analogues. In order to investigate the mechanism of such a peripheral neuropathy, the effects of 1-100 micromol/l oxaliplatin were assessed on the nodal ionic currents of single frog myelinated axons as a model of peripheral excitable membranes. Oxaliplatin decreased both Na(+) and K(+) currents in a dose-dependent manner and within 5-10 min, without producing any marked changes in the current kinetics. It was about three to eight times more effective in reducing the Na(+) than the K(+) current. In addition, it shifted the voltage-dependence of both Na(+) and K(+) conductances towards negative membrane potentials. A negative shift in the steady-state inactivation-voltage curve of the peak Na(+) current was also observed in the presence of oxaliplatin. These effects were not reversed by washing the myelinated axons with an oxaliplatin-free solution for at least 30 min. It is concluded that oxaliplatin modifies the voltage-dependent ionic channels mainly by altering the external surface membrane potential. The knowledge of such a mechanism may help to counteract the neurotoxic action of this anticancer agent.
Benoit
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Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR 9040, CNRS, bât. 32-33, 91198 Gif-sur-Yvette cedex, France. benoit@nbcm.cnrs-gif.fr
Brienza
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Dubois
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D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001369:Axons / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000077150:Oxaliplatin; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D011893:Rana esculenta; D011901:Ranvier's Nodes / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000077150:Oxaliplatin