Block of deltamethrin-modified sodium current in cultured mouse neuroblastoma cells: local anesthetics as potential antidotes

doi:10.1016/0006-8993(90)90947-A

Brain Research

Volume 518, Issues 1–2, 4 June 1990, Pages 11-18

https://doi.org/10.1016/0006-8993(90)90947-A Get rights and content

Abstract

Effects of local anesthetics and anticonvulsants on the pyrethroid-modified sodium current in cultured mouse neuroblastoma cells have been investigated using the suction pipette voltage clamp technique. In the presence of 10 μM of the pyrethroid deltamethrin the sodium current consists of an enhanced peak current during membrane depolarization and a slowly decaying, deltamethrin-induced tail current remaining after repolarization. At the onset of block the local anesthetics tetracaine, lidocaine and QX 314 reduced the deltamethrin-induced tail current more effectively than the peak current. Lidocaine, but not phenytoin, caused a time-dependent block of tail currents evoked by membrane depolarizations lasting 10–1000 ms. Both lidocaine- and phenytoin-induced blocks were independent of the membrane potential during the tail current. The anticonvulsants phenytoin, phenobarbital and valproate blocked the tail and the peak sodium current to the same extent, but diazepam, mephenesin and urethane blocked the peak current more effectively. Vitamin E, which suppresses pyrethroid-induced paresthesia of the skin, had no effect on the voltage-dependent sodium current. It is concluded that indirect effects of anticonvulsants on pyrethroid-induced toxic symptoms predominate, whereas local anesthetics preferentially block the pyrethroid-induced tail current. Therefore, local anesthetics are potentially useful pyrethroid antidotes.

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Citation Excerpt :
An ideal therapeutic agent would antagonize the abnormal, pyrethroid-evoked sodium current but leave the normal one unchanged. In a survey of the relative ability of a range of drugs to antagonize the deltamethrin-evoked and normal sodium currents in neuroblastoma cells (Oortgiesen et al., 1990), it was found that tetracaine and lidocaine were particularly effective. Lidocaine was also effective at antagonizing deltamethrin effects in intact rat hippocampus (Joy et al., 1990), and procainamide modestly effective against motor signs (Bradbury et al., 1983), but local anesthetics are not practical for systemic therapy because of their cardiotoxicity.
The pyrethroids are a widely used class of insecticides to which there is significant human exposure. They are however generally regarded as safe to man, and there have been few reports of human fatalities. Their acute toxicity is dominated by pharmacological actions upon the central nervous system (CNS), predominantly mediated by prolongation of the kinetics of voltage-gated sodium channels, although other mechanisms operate. This review summarizes our present understanding of such actions and the pharmacological options to antagonize them. One significant problem is the very clear heterogeneity of pyrethroid sensitivity that is seen across sodium channel subtypes; however, the distribution and function of these across the central nervous system are poorly characterized. The review also provides an overview of recent studies that suggest additional effects of pyrethroids: developmental neurotoxicity, the production of neuronal death, and action mediated via pyrethroid metabolites. The evidence for these is at present equivocal, but all 3 carry important implications for human health.
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Block of deltamethrin-modified sodium current in cultured mouse neuroblastoma cells: local anesthetics as potential antidotes

Abstract

Neuropharmacology

Toxicol. Appl. Pharmacol.

J. Biophys.

Pestic. Biochem. Physiol.

Pestic. Biochem. Physiol.

Brain Research

Toxicol. Appl. Pharmacol.

J. Neurosci. Methods

Pestic. Biochem. Physiol.

Brain Research

Pestic. Biochem. Physiol.

Pestic. Biochem. Physiol.

Brain Research

Biophys. J.

Brain Research

Neurotransmitter synthesis by neuroblastoma clones

Molecular properties of sodium channels in excitable membranes

Stabilization of sodium channel states by deltamethrin in mouse neuroblastoma cells

J. Physiol. (Lond.)

Effet antagoniste du phenprobamate et du carbamate de méphénésine sur l'intoxicationàla deltaméthrine

J. Toxicol. Clin. Exp.