Ion channels are the primary target sites for several classes of natural and synthetic insecticidal compounds. The voltage-sensitive sodium channel is the major target site for DDT and pyrethroids, the veratrum alkaloids, and N-alkylamides. Recently, neurotoxic proteins from arthropod venoms, some of which specifically attack insect sodium channels, have been engineered into baculoviruses to act as biopesticides. The synthetic pyrazolines also primarily affect the sodium channel, although some members of this group target neuronal calcium channels as well. The ryanoids have also found use as insecticides, and these materials induce muscle contracture by irreversible activation of the calcium-release channel of the sarcoplasmic reticulum. The arylheterocycles (e.g. endosulfan and fipronil) are potent convulsants and insecticides that block the GABA-gated chloride channel. In contrast, the avermectins activate both ligand- and voltage-gated chloride channels, which leads to paralysis. At field-use rates, a neurotoxic effect of the ecdysteroid agonist RH-5849 is observed that involves blockage of both muscle and neuronal potassium channels. The future use of ion channels as targets for chemical and genetically engineered insecticides is also discussed.

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, lambda-cyhalothrin, beta-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.

Pyrethroid insecticides are one of the most widely used classes of insecticides. Previous studies revealed that pyrethroids potently affect the insect voltage-gated sodium (Na(+)) channel (VGSC), resulting in prolonged channel open time. However, recent findings have suggested that pyrethroids may affect targets other than the VGSC. In particular, several studies have shown that pyrethroids can modulate the activity of voltage-gated calcium (Ca(2+)) channels (VGCCs). However, these studies often reported conflicting results; some studies observed stimulatory effects, whereas others observed inhibitory effects of pyrethroids on VGCCs. This study investigated whether allethrin (AL), a well-characterized type I pyrethroid, altered VGCC characteristics measured by whole-cell recording in rat pheochromocytoma cells (PC12) differentiated with nerve growth factor (NGF). AL (5 microM) increased peak, end, and tail composite VGCC current independent of its effects on VGSCs. After blocking VGCC subtype-specific current with omega-conotoxin GVIA (GVIA, an N-type VGCC antagonist) or nimodipine (NIM, an L-type VGCC antagonist), our data further suggest that AL differentially affects VGCC subtypes. Thus, AL apparently stimulated GVIA-insensitive current while inhibiting NIM-insensitive current. AL also significantly altered the voltage dependency of activation and inactivation of L-type VGCCs. The differential modulation of VGCC subtypes by AL may explain some of the conflicting observations of other studies.

The phytogenic algicide sanguinarine shows strong inhibitory effects on some bloom-forming cyanobacteria and exhibits great potential in cyanobacterial bloom mitigation. To evaluate the possible ecological effects of sanguinarine on microalgae, the effects and possible mechanisms of sanguinarine on the competition between bloom-forming cyanobacterium Raphidiopsis raciborskii (formerly named Cylindrospermopsis raciborskii) and green alga Scenedesmus obliquus were investigated through co-culture competition test and comparative toxicological study including growth characteristics, chlorophyll fluorescence transients, activities of antioxidant enzymes, and lipid peroxidation. The results of Raphidiopsis-Scenedesmus co-culture competition test showed that sanguinarine decreased the competition ability of R. raciborskii, which benefitted S. obliquus in winning the competition. Toxicological studies have shown that sanguinarine exhibited high inhibitory effects on the growth and photosynthesis of R. raciborskii but no obvious toxicity on S. obliquus at concentrations of no more than 80 mug L(-1). Oxidative damage partially contributed but was not the primary mechanism for the toxicity of sanguinarine on R. raciborskii. The results presented in this study indicate that sanguinarine may be a good algicidal candidate in mitigation of Raphidiopsis-based water bloom.

Potassium transport across synaptosomes was studied under the influence of two synthetic pyrethroids, (Permethrin, without the cyano group) and Cypermethrin (CPM, with the cyano group). Synaptosomes were isolated from rat brain cerebral cortex and incubated with 40 microM of PM and CPM for 15 min at 37 degrees C. K+ release was monitored by a K(+)-sensitive electrode. CPM caused more K+ release from synaptosomes compared to PM. K+ transport is regulated by Na(+)-K(+)-ATPase, K(+)-ATPase and K+ channels. To understand the mode of action, synaptosomes were preincubated with 9.5 x 10(-3) M ouabain (inhibitor of Na(+)-K(+)-ATPase), 1.7 x 10(-2) M N-ethylmaleamide (K(+)-ATPase inhibitor), and 9.5 x 10(-5) M quinine sulfate (K(+)-channel blocker) for 15 min at 37 degrees C. In the presence of ouabain and N-ethylmaleamide, PM- and CPM-induced K+ release was decreased and in the presence of quinine sulfate, there was no release of K+. Furthermore, the studies indicated that PM and CPM significantly decreased K+ uptake.

The Food Quality Protection Act (FQPA) of 1996 requires the United States Environmental Protection Agency to consider the cumulative effects of exposure to pesticides having a 'common mechanism of toxicity.' This paper reviews the information available on the acute neurotoxicity and mechanisms of toxic action of pyrethroid insecticides in mammals from the perspective of the 'common mechanism' statute of the FQPA. The principal effects of pyrethroids as a class are various signs of excitatory neurotoxicity. Historically, pyrethroids were grouped into two subclasses (Types I and II) based on chemical structure and the production of either the T (tremor) or CS (choreoathetosis with salivation) intoxication syndrome following intravenous or intracerebral administration to rodents. Although this classification system is widely employed, it has several shortcomings for the identification of common toxic effects. In particular, it does not reflect the diversity of intoxication signs found following oral administration of various pyrethroids. Pyrethroids act in vitro on a variety of putative biochemical and physiological target sites, four of which merit consideration as sites of toxic action. Voltage-sensitive sodium channels, the sites of insecticidal action, are also important target sites in mammals. Unlike insects, mammals have multiple sodium channel isoforms that vary in their biophysical and pharmacological properties, including their differential sensitivity to pyrethroids. Pyrethroids also act on some isoforms of voltage-sensitive calcium and chloride channels, and these effects may contribute to the toxicity of some compounds. Effects on peripheral-type benzodiazepine receptors are unlikely to be a principal cause of pyrethroid intoxication but may contribute to or enhance convulsions caused by actions at other target sites. In contrast, other putative target sites that have been identified in vitro do not appear to play a major role in pyrethroid intoxication. The diverse toxic actions and pharmacological effects of pyrethroids suggest that simple additivity models based on combined actions at a single target are not appropriate to assess the risks of cumulative exposure to multiple pyrethroids.

A novel series of acyclic imine-substituted nitenpyram analogues were designed and synthesized from nitroaminoguanidine, and their structures were confirmed using X-ray diffraction crystallography. Preliminary bioassays showed that the target molecules exhibited good activities against aphids in laboratory (Myzus persicae Sulzer) and field trials (M. persicae Sulzer and Brevicoryne brassicae Linnaeus). Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to develop a three-dimensional quantitative structure-activity relationship model that describes the insecticidal activity of 21 neonicotinoid derivatives. Simple synthesis, low cost, and good insecticidal activity have made this series of compounds become very promising candidates for future commercial pesticides.

Sodium channel inhibitor (SCI) insecticides were discovered almost four decades ago but have only recently yielded important commercial products (eg., indoxacarb and metaflumizone). SCI insecticides inhibit sodium channel function by binding selectively to slow-inactivated (non-conducting) sodium channel states. Characterization of the action of SCI insecticides on mammalian sodium channels using both biochemical and electrophysiological approaches demonstrates that they bind at or near a drug receptor site, the

The effects of cyhalothrin on the delayed rectifier potassium current in the central neurons of Helicoverpa armigera were studied using the patch clamp technique for the first time. The results showed that before application of cyhalothrin, 81% and 39% cells were activated at -30 mV and -40 mV (n=21), respectively. In 15 min after cyhalothrin (10-5 mmol/L) application, 63% and 38% cells were activated at -40 mV and -50 mV (n=8), respectively. The amplitude of the current decreased significantly after application of cyhalothrin and the inhibition percentage reached 37.7% in 1 min (n=19). After the application, activation curve shifted to the negative direction and the value of Vh changed significantly, but the k value did not change remarkably. In conclusion, the results suggest that under the action of cyhalothrin, the potassium channels can be activated more easily and current amplitude can be inhibited significantly, this is related to the nervous insensitivity，and potassium channels of Helicoverpa armigera central neurons are the action targets of pyrethroid insecticides.]]>