Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons.

Pyrethroid insecticides bind to voltage-gated sodium channels (VGSCs) and modify their gating kinetics, thereby disrupting neuronal function. Pyrethroids have also been reported to alter the function of other channel types, including activation of voltage-gated calcium channels. Therefore, the present study compared the ability of 11 structurally diverse pyrethroids to evoke Ca(2+) influx in primary cultures of mouse neocortical neurons. Nine pyrethroids (tefluthrin, deltamethrin, λ-cyhalothrin, β-cyfluthrin, esfenvalerate, S-bioallethrin, fenpropathrin, cypermethrin, and bifenthrin) produced concentration-dependent elevations in intracellular calcium concentration ([Ca(2+)](i)) in neocortical neurons. Permethrin and resmethrin were without effect on [Ca(2+)](i). These pyrethroids displayed a range of efficacies on Ca(2+) influx; however, the EC(50) values for active pyrethroids all were within one order of magnitude. Tetrodotoxin blocked increases in [Ca(2+)](i) caused by all nine active pyrethroids, indicating that the effects depended on VGSC activation. The pathways for deltamethrin- and tefluthrin-induced Ca(2+) influx include N-methyl-D-aspartic acid receptors, L-type Ca(2+) channels, and reverse mode of operation of the Na(+)/Ca(2+) exchanger inasmuch as antagonists of these sites blocked deltamethrin-induced Ca(2+) influx. These data demonstrate that pyrethroids stimulate Ca(2+) entry into neurons subsequent to their actions on VGSCs.