Anisatin modulation of the γ‐aminobutyric acid receptor‐channel in rat dorsal root ganglion neurons

Ikeda, Tomoko; Ozoe, Yoshihisa; Okuyama, Emi; Nagata, Keiichi; Honda, Hiroshi; Shono, Toshiyuki; Narahashi, Toshio

doi:10.1038/sj.bjp.0702700

Cited by 58 publications

(78 citation statements)

References 41 publications

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“…Fipronil is known to block the GABA A receptor in rat DRG neurons with an IC 50 value of 1.6 M (Ikeda et al, 2001). It blocks both the resting receptors and activated receptors to the same extent.…”

Section: Resultsmentioning

confidence: 99%

“…Both dieldrin and fipronil potently blocked the insect GABA-gated chloride channels at nanomolar concentrations. Compared with our previous studies with rat dorsal root ganglion (DRG) neurons Ikeda et al, 2001), the blocking action of fipronil on cockroach GABA receptors was much more potent than its action on mammalian GABA A receptors. In contrast, the action of dieldrin on insect GABA receptors was similar to its actions on mammalian GABA A receptors, exhibiting a dual action on GABA-induced chloride currents that manifested as an initial enhancement followed by a dramatic inhibition.…”

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confidence: 86%

“…1), a phenylpyrazole compound, was developed in the mid-1990s and became an excellent insecticide, mainly due to its high effectiveness against some of the dieldrin-resistant strains of insects and its low toxicity to mammals (Tingle et al, 2003). Although both fipronil and dieldrin are known to block GABA receptors (Millar et al, 1994;Hosie et al, 1995;Ikeda et al, 2001), the mechanisms of their high and selective toxicity against insects are not fully understood. Our hypothesis is that the differential sensitivities of the GABA receptors in insect and mammalian neurons are the basis of the selective toxicity of fipronil and dieldrin.…”

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confidence: 99%

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Differential Actions of Fipronil and Dieldrin Insecticides on GABA-Gated Chloride Channels in Cockroach Neurons

Zhao

Salgado

Yeh³

et al. 2003

J Pharmacol Exp Ther

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Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABA A receptors to fipronil and dieldrin. We examined differential actions of fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABA A receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC 50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC 50 value of 4 nM followed by inhibition with an IC 50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABA A receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABA A receptors. It was concluded that the higher toxicity of fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.The selective toxicity between mammals and insects is one of the most important factors for the development of new insecticides. In fact, most insecticides on the market are more toxic to insects than to mammals. However, the mechanisms underlying high insecticidal activity and low mammalian toxicity of insecticides are not fully understood. Although the selective toxicity of certain insecticides (e.g., organophosphates) is due primarily to the differences in metabolism (O'

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Section: Resultsmentioning

confidence: 99%

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confidence: 86%

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confidence: 99%

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Differential Actions of Fipronil and Dieldrin Insecticides on GABA-Gated Chloride Channels in Cockroach Neurons

Zhao

Salgado

Yeh³

et al. 2003

J Pharmacol Exp Ther

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120

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“…Fipronil is known to block GABA receptors thereby causing hyperexcitation of insects and mammals (Ikeda et al, 2001;Zhao et al, 2003). Fipronil has also been found to be a potent blocker of GluCls (Zhao et al, 2004a, b;.…”

Section: Glutamate-activated Chloride Channel: Unique Chemical Targetmentioning

confidence: 99%

Use of non-mammalian alternative models for neurotoxicological study

et al. 2008

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The field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals, and resource limitations and ethical concerns associated with testing using traditional mammalian species. National and international government agencies have defined a need to reduce, refine or replace mammalian species in toxicological testing with alternative testing methods and non-mammalian models. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expense and using fewer mammals. Recent advances in genetic technologies and the strong conservation between human and non-mammalian genomes allows for the dissection of the molecular pathways involved in neurotoxicological responses and neurological diseases using genetically tractable organisms. In this review, applications of four non-mammalian species, Zebrafish, cockroach, Drosophila, and Caenorhabditis elegans, in the investigation of neurotoxicology and neurological diseases are presented.

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“…We previously reported that naturally occurring terpenoids such as picrodendrins and anisatin exhibit insecticidal activity by binding to the antagonist site of the GABA receptor. [2][3][4][5] Several terpene lactones such as picrodendrin O exhibited selective affinity for the insect versus mammalian GABA receptors. We have also isolated insecticidal alkaloid GABA antagonists from the culture of Aspergillus terreus by binding assay-guided screening.…”

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Isocoumarin Derivative as a Novel GABA Receptor Ligand from Neosartorya quadricincta

et al. 2004

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The receptor for the inhibitory neurotransmitter GABA is known as a target for such insecticides and acaricides as fipronil and avermectins.1) These insecticides selectively act on the insect GABA receptor, and thus are toxic to insects but not mammals. We previously reported that naturally occurring terpenoids such as picrodendrins and anisatin exhibit insecticidal activity by binding to the antagonist site of the GABA receptor. [2][3][4][5] Several terpene lactones such as picrodendrin O exhibited selective affinity for the insect versus mammalian GABA receptors. We have also isolated insecticidal alkaloid GABA antagonists from the culture of Aspergillus terreus by binding assay-guided screening.6) This earlier screening convinced us that our fungal cultures are a rich source of GABAergic or anti-GABAergic compounds.We report here on the subsequent isolation and structural elucidation of a novel ligand for the insect GABA receptor. MATERIALS AND METHODS InstrumentsThe NMR spectra were recorded on a JEOL GSX400 instrument. Mass spectra were obtained on a JEOL JMS-700 spectrometer. The UV and IR spectra were measured on Shimadzu UV-260 and FTIR-8100 spectrophotometers, respectively. Optical rotations were obtained on a JASCO DIP-370 polarimeter. Observations by electron microscopy were performed with a JEOL JSM-6300F electron microscope. Taxonomic StudiesTaxonomic studies of strain PF1223 were performed according to the method of Horie et al.7) The fungal strain PF1223 was deposited at the National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology, Japan, under the accession number FERM P-17658. FermentationStrain PF1223 was inoculated from an agar slant into a 100-ml Erlenmeyer flask containing 20 ml of a seed medium made up of 1.0% starch, 1.0% glucose, 0.6% wheat germ, 0.2% soybean meal, 0.3% yeast extract, 0.5% polypeptone, 0.2% CaCO 3 , and tap water (pH 7.0 before sterilization). The inoculated flask was shaken on a rotary shaker (200 rpm) at 25°C Matsue, Shimane 690-8504, Japan † Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Kanagawa 222-8567, Japan (Received April 27, 2004; Accepted June 2, 2004) For the purpose of discovering GABA receptor-directed insecticides in natural products, fungal culture extracts were screened for their ability to inhibit the specific binding of the noncompetitive antagonist [ 3 H]EBOB to housefly head membranes. The screening efforts led to the isolation of a derivative of dihydroisocoumarin (PF1223) from the culture of Neosartorya quadricincta. This compound at 2.2 mM inhibited [3 H]EBOB binding by 65%. This ligand might prove to be a lead compound for the identification of novel insecticides acting at the insect GABA receptor.

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Anisatin modulation of the γ‐aminobutyric acid receptor‐channel in rat dorsal root ganglion neurons

Cited by 58 publications

References 41 publications

Differential Actions of Fipronil and Dieldrin Insecticides on GABA-Gated Chloride Channels in Cockroach Neurons

Differential Actions of Fipronil and Dieldrin Insecticides on GABA-Gated Chloride Channels in Cockroach Neurons

Use of non-mammalian alternative models for neurotoxicological study

Isocoumarin Derivative as a Novel GABA Receptor Ligand from Neosartorya quadricincta

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