Polychlorocycloalkane insecticide-induced convulsions in mice in relation to disruption of the GABA-regulated chloride ionophore

doi:10.1016/0024-3205(86)90295-X

Life Sciences

Volume 39, Issue 20, 17 November 1986, Pages 1855-1862

https://doi.org/10.1016/0024-3205(86)90295-X Get rights and content

Abstract

The toxicity to mice of intraperitoneally-administered polychlorocycloalkane (PCCA) insecticides is generally correlated with their potency as $in vitro$ inhibitors of the brain specific [³⁵S]- $t$ -butylbicyclophosphorothionate ([³S]TBPS) binding site with correction for metabolic activation and detoxification. These findings from our earlier studies are extended here to $in vivo$ investigations relating convulsant action to inhibition of the TBPS binding site in poisoned mice. Radioligand binding assays involved brain P₂ membranes washed three times with 1 mM EDTA to remove endogenous γ-aminobutyric acid (GABA) or other modulator(s) which otherwise serves as a noncompetitive inhibitor of [³⁵S]-TBPS binding at the GABA-regulated chloride ionophore. Examination of lindane, technical toxaphene, toxaphene toxicant A, and 10 polychlorocyclodiene insecticides revealed 62 ± 4% binding site inhibition 30 min after their LD₅₀ doses with 32 ± 3% inhibition at one-half and 6 ± 3% inhibition at one-quarter of their LD₅₀ doses. This correlation between binding site inhibition and convulsant action is also evident in dose- and time-dependency studies with endosulfan sulfate. The brain P₂ membranes of treated mice contain the parent compound with each of the PCCAs plus activation products of some of the cyclodienes, $i.e.$ endosulfan sulfate from α- and ß-endosulfan and 12-ketoendrin from isodrin and endrin. The finding that the brains of treated mice contain sufficient PCCA or its activation products to achieve a magnitude of [³⁵S]TBPS binding site inhibition correlated with the severity of the poisoning signs supports the hypothesis that the acute toxicity of PCCA insecticides to mammals is due to disruption of the GABA-regulated chloride ionophore.

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The basis for the high in vivo seizurogenic potency of TETS is not understood. TETS is markedly more potent than PTZ, but not substantially more potent than PTX, in displacing the GABAAR ligand [35S]t-butylbicyclophosphorothionate in rat brain membranes (Cole and Casida, 1986; Esser et al., 1991; Ratra et al., 2001; Squires et al., 1984). TETS and picrotoxin are similarly potent in inhibiting GABAAR-mediated GABA-activated chloride ion uptake by membrane vesicles from rat cerebral cortex (Obata et al., 1988).
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Citation Excerpt :
GABAA receptors are members of the superfamily of ligand-gated ion channels that contain a chloride ionophore; by binding to these receptors, endogenous GABA causes the opening of chloride channels resulting in hyperpolarization of the membrane. Lindane and cyclodienes bind to a specific site (the picrotoxin site) on the chloride channel, thereby blocking its opening and thus antagonizing the “inhibitory” action of GABA (Cole and Casida, 1986; Eldefrawi and Eldefrawi, 1987; Narahashi et al., 2007). Treatment of acute poisoning is symptomatic; phenobarbital and diazepam can be used as anticonvulsants.
Organochlorine and pyrethroid compounds represent an old and a new class, respectively, of insecticides. Organochlorines such as DDT, dieldrin, or chlordecone, have been banned, primarily because of environmental issues. DDT is still used in certain countries to fight malaria-bearing mosquitoes, while lindane still finds some limited used against head lice. In contrast, pyrethroids find widespread use because of their efficacy, low environmental persistence, and relatively low mammalian toxicity. Like all insecticides, organochlorines and pyrethroids target the nervous system of insects and of nontarget species. All pyrethroids and DDT interact with the sodium channel; by keeping it open longer, they increase the likelihood of action potentials developing, thus creating a condition of hyperexcitability, whose main clinical sign is tremors. Most other organochlorines (except chlordecone), as well as certain (type II) pyrethroids, block the chloride channels of the GABA-A receptor, and cause seizures. Evidence of an association between exposure to organochlorine and pyrethroid insecticides and neurodegenerative diseases (e.g., Parkinson's disease) is weak, at best.
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In addition, a wide array of molecular targets of this insecticide have been discovered in the endocrine (Wozniak et al., 2005) and immunological systems (Aggarwal et al., 2008). The mechanism of neurotoxicity of endosulfan appears to be dominated by its capacity to inhibit non-competitively the GABA-A type of receptors (Cole and Casida, 1986; Chen et al., 2006) although other targets are believed to exist (Sunol et al., 2008; Paul et al., 1994; Vale et al., 2003). GABA-A receptors are pentameric proteins formed by various combinations of 19 receptor subunits in mammals, each attributed to a different gene (Simon et al., 2004).
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^☆: This research was supported in part by NIH grant P01 ES00049.

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Polychlorocycloalkane insecticide-induced convulsions in mice in relation to disruption of the GABA-regulated chloride ionophore☆

Abstract

Life Sci.

Pestic. Biochem. Physiol.

Comp. Biochem. Physiol.

Biochem. Biophys. Res. Commun.

Neuroscience Lett.

Neuropharmacol.

Life Sci.