The objective of this research is to elucidate the mechanism of action of insecticides on the nerve membrane which is the most critical target site of a variety of insecticides. Advanced electrophysiological techniques developed in our laboratory for the study of insecticides will be fully utilized, including intracellular microelectrode, voltage clamp, intracellular perfusion, and gating current measurement. The insecticides used for this study are a variety of synthetic pyrethroids and DDT and its analogs and derivatives. The proposed study is divided into nine specific projects. 1) Kinetics of insecticide-sodium channel interactions will be analyzed using voltage clamp methods. 2) The actions of two types of pyrethroids, one being a stimulating type and the other depolarizing type, will be characterized. 3) The structure-activity relationship of pyrethroids will be established for the two types of action. 4) The mechanism by which isomers exert differential effects will be studied. 5) DDT and its analogs will be compared with pyrethroids to determine similarities and differences in action. 6) The effects of pyrethroids and DDT on gating current will be studied. 7) Ionic selectivity of the sodium cnannels modified by pyrethroids will be determined. 8) The effects of two types of pyrethroids on synapses and sensory cells will be studied to find out common features of the two types in exerting symptoms of poisoning. 9) The mechanism underlying the effects of temperature on pyrethroid and DDT action will be studied using voltage clamp methods. These studies are expected to provide the basis for the molecular mechanism of action of insecticides and clues to improvement of the existing insecticides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS014143-09
Application #
3395422
Study Section
Toxicology Study Section (TOX)
Project Start
1978-05-01
Project End
1986-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
School of Medicine & Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Narahashi, Toshio; Zhao, Xilong; Ikeda, Tomoko et al. (2010) Glutamate-activated chloride channels: Unique fipronil targets present in insects but not in mammals. Pestic Biochem Physiol 97:149-152
Peterson, Randall T; Nass, Richard; Boyd, Windy A et al. (2008) Use of non-mammalian alternative models for neurotoxicological study. Neurotoxicology 29:546-55
Narahashi, T; Zhao, X; Ikeda, T et al. (2007) Differential actions of insecticides on target sites: basis for selective toxicity. Hum Exp Toxicol 26:361-6
Zhao, Xilong; Yeh, Jay Z; Salgado, Vincent L et al. (2005) Sulfone metabolite of fipronil blocks gamma-aminobutyric acid- and glutamate-activated chloride channels in mammalian and insect neurons. J Pharmacol Exp Ther 314:363-73
Zhao, Xilong; Ikeda, Tomoko; Salgado, Vincent L et al. (2005) Block of two subtypes of sodium channels in cockroach neurons by indoxacarb insecticides. Neurotoxicology 26:455-65
Ikeda, Tomoko; Nagata, Keiichi; Kono, Yoshiaki et al. (2004) Fipronil modulation of GABAA receptor single-channel currents. Pest Manag Sci 60:487-92
Zhao, Xilong; Salgado, Vincent L; Yeh, Jay Z et al. (2004) Kinetic and pharmacological characterization of desensitizing and non-desensitizing glutamate-gated chloride channels in cockroach neurons. Neurotoxicology 25:967-80
Zhao, Xilong; Yeh, Jay Z; Salgado, Vincent L et al. (2004) Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. J Pharmacol Exp Ther 310:192-201
Zhao, Xilong; Ikeda, Tomoko; Yeh, Jay Z et al. (2003) Voltage-dependent block of sodium channels in mammalian neurons by the oxadiazine insecticide indoxacarb and its metabolite DCJW. Neurotoxicology 24:83-96
Ikeda, Tomoko; Zhao, Xilong; Kono, Yoshiaki et al. (2003) Fipronil modulation of glutamate-induced chloride currents in cockroach thoracic ganglion neurons. Neurotoxicology 24:807-15

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