Abstract：
The dinoflagellate Karenia brevis is a causative agent of red tides in the Gulf of Mexico and generates a potent family of structurally related brevetoxins that act via the voltage-sensitive Na+ channel. This project was undertaken to better understand the neurotoxicology and kdr cross-resistance to brevetoxins in house flies by comparing the susceptible aabys strain to ALkdr (kdr) and JPskdr (super-kdr). When injected directly into the hemocoel, larvae exhibited rigid, non-convulsive paralysis consistent with prolongation of sodium channel currents, the known mechanism of action of brevetoxins. In neurophysiological studies, the firing frequency of susceptible larval house fly central nervous system preparations showed a > 200% increase 10 min after treatment with 1 nM brevetoxin-3. This neuroexcitation is consistent with the spastic paralytic response seen after hemocoel injections. Target site mutations in the voltage-sensitive sodium channel of house flies, known to confer knockdown resistance (kdr and super-kdr) against pyrethroids, attenuated the effect of brevetoxin-3 in baseline firing frequency and toxicity assays. The rank order of sensitivity to brevetoxin-3 in both assays was aabys > ALkdr > JPskdr. At the LD50 level, resistance ratios for the knockdown resistance strains were 6.9 for the double mutant (super-kdr) and 2.3 for the single mutant (kdr). The data suggest that knockdown resistance mutations may be one mechanism by which flies survive brevetoxin-3 exposure during red tide events.
摘要：
鞭毛藻Kareniabrevis是墨西哥湾赤潮的病原体，可产生有效的结构相关的短毒素家族，这些毒素通过电压敏感的Na通道起作用。通过将易感的aabys菌株与ALkdr（kdr）和JPskdr（super-kdr）进行比较，进行了该项目，以更好地了解家蝇对短毒素的神经毒理学和kdr交叉抗性。当直接注射到血液中时，幼虫表现出僵硬，非抽搐性麻痹与钠通道电流延长一致，已知的brevetoxins的作用机制。在神经生理学研究中,用1nMbrevetoxin-3处理后10分钟，易感幼虫家蝇中枢神经系统制剂的放电频率增加>200％。这种神经兴奋与注入血液后看到的痉挛性麻痹反应一致。家蝇电压敏感钠通道靶位点突变,已知赋予对拟除虫菊酯的击倒抗性（kdr和super-kdr），减弱了brevetoxin-3在基线发射频率和毒性测定中的作用。在两种测定中，对brevetoxin-3的敏感性的等级顺序为aabys>ALkdr>JPskdr。在LD50水平，双突变体（super-kdr）的敲低抗性菌株的抗性比率为6.9，单突变体（kdr）的抗性比率为2.3。数据表明，敲低抗性突变可能是苍蝇在赤潮事件中存活的一种机制。
