The purpose of this research was to explore the possibility of co-applying pyrethroids (agonists of voltage-sensitive sodium channels) with the potassium channel blockers potassium channel blockers 2S-65465 (2S), 4-aminopyridine (4-AP), and quinidine in order to potentiate the neurological effect of pyrethroids and reduce the amount of chemical needed for effective control of Anopheles gambiae. We hypothesize that the ability of pyrethroids to cause persistent sodium currents will be augmented by blockage of outward potassium current flow, which normally repolarizes the membrane potential during a nerve membrane action potential. Topical treatments to An. gambiae, and LD10s (10% mortality dose) of synergists as co-applications were used. 2S showed the best synergism with permethrin (8.6-fold) and deltamethrin (7.2-fold), while PBO (2.2-fold) and 4-AP (2.2-fold) moderately synergized pyrethroids, and quinidine had no effect. In a fluorescence assay of cytochrome P450 activity, PBO inhibited at 1 mM, while 2S had no activity at 3 mM, suggesting inhibition of P450 activity was not involved in 2S synergism. In electrophysiological recordings of Periplaneta americana giant axons, 2S (10 µM) and 4-AP (30 µM) caused multiple spikes after a single stimulation. Permethrin at 10 µM showed significant summating depolarization (3.0 ± 0.4 mV) after a train of 10 stimuli were applied at 5 Hz, and deltamethrin at 0.03 µM showed significant depolarization of 3.2 ± 1.4 mV without stimulation. 2S at 0.3 µM and 4-AP at 1 to 3 µM synergized the effects of 3 µM permethrin and 0.01 µM deltamethrin. The potassium channel mutant of Drosophila melanogaster Sh5 showed 5- and 35-fold higher sensitivity to permethrin and deltamethrin, respectively, than wild-type in glass contact assays. On the other hand, toxicity responses of the Kv2 mutant, Shab3, were not different from that of the wild-type strain. These findings correlated with larval CNS recordings, in which the Sh5 strain showed significantly greater (P &lt; 0.05) excitation to 1 nM PM, while the CSOR and Shab3 strains showed no effect on the PM response. Thus, Kv1 channels seem to be a better target for pyrethroid synergism. In conclusion, co-application of potassium channel blockers 2S and 4-AP with pyrethroids can synergistically increase the mosquitocidal activities on An. gambiae, and these activities are correlated with synergism on the axon and ion channel levels.

Synergistic effects of potassium channel blockers and pyrethroids: Mosquitocidal activity and neuronal mode of action

2019 Fall National Meeting

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