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 ([Ca²⁺]i) in neocortical neurons. Permethrin and resmethrin were without effect on [Ca²⁺]i. These pyrethroids displayed a range of efficacies on Ca²⁺ influx; however, the EC ₅₀ values for active pyrethroids all were within one order of magnitude. Tetrodotoxin blocked increases in [Ca²⁺]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 ⁺/Ca²⁺ exchanger inasmuch as antagonists of these sites blocked deltamethrin-induced Ca²⁺ influx. These data demonstrate that pyrethroids stimulate Ca²⁺ entry into neurons subsequent to their actions on VGSCs.