Convulsions Induced by Lindane and the Involvement of the GABAergic System

Cattabeni, Flaminio; Pastorello, M; Eli, Maynur

doi:10.1007/978-3-642-69083-9_44

Cited by 18 publications

(4 citation statements)

References 9 publications

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“…The finding in the present report that lindane cytotoxicity in neocortical neurons is primarily associated with an interaction between lindane and the allosteric coupling between GABA and benzodiazepines at the GABA A receptor, is in line with the well-documented action of lindane on GABA A receptors and GABAmediated Clfluxes in a variety of neural preparations in vivo and in vitro (Cattabeni et al, 1983;Cole and Casida, 1986;Llorens et al, 1990;Pomés et al, 1994a;Vale et al, 1997). The slight protective action of baclofen may, however, point to an additional action of lindane involv-ing GABA B receptors, a mechanism much more pronounced in other types of neurons (Vale et al, 1998).…”

Section: Discussionsupporting

confidence: 90%

“…Although lindane does not inhibit binding of [ 3 H]flunitrazepam, [ 3 H]GABA or [ 3 H]muscimol (Cattabeni et al, 1983;Abalis et al, 1985;Vale et al, 1997), it interacts with the allosteric coupling between GABA and benzodiazepine binding sites. Thus, lindane reduces the increase in [ 3 H]flunitrazepam binding induced by GABA (Vale et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic action of lindane in neocortical GABAergic neurons is primarily mediated by interaction with flunitrazepam-sensitive GABAA receptors

Vale

Damgaard²,

Suñol

et al. 1998

J. Neurosci. Res.

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The cytotoxic action of the gamma-isomer of hexachlorocyclohexane (y-HCH; lindane) was studied in cultured mouse neocortical neurons by measurements of the reduction in mitochondrial function using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. The cells were exposed to 30-300 microM lindane in the culture medium for different periods of time and lindane cytotoxicity was found to be time- and concentration-dependent. Lindane cytotoxicity could be ameliorated by addition of gamma aminobutyric acid (GABA) in a concentration-dependent manner but this effect of GABA was not blocked by bicuculline or picrotoxinin (PTX). Lindane induced cytotoxicity was also reduced by the GABA(A) receptor agonists muscimol and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol). This effect was enhanced by the simultaneous presence of flunitrazepam but only at the highest lindane concentrations studied (200 and 300 microM). Flunitrazepam by itself had no effect on lindane-induced cytotoxicity. The protective effect of GABA plus flunitrazepam was blocked by the benzodiazepine receptor antagonist flumazenil and by the GABA(A) antagonist bicuculline, suggesting the involvement of central benzodiazepine receptors allosterically coupled to the GABA recognition site at the GABA(A) receptor. When 100 microM PTX was used to suppress the protective effect of GABA and flunitrazepam, a significant effect of PTX was observed only at 300 microM lindane. The GABA(B) receptor agonist, baclophen, only marginally reduced the cytotoxic effect induced by the highest lindane concentrations. It is concluded that the cytotoxic action of lindane in neocortical neurons in culture is mediated primarily through an interaction with allosterically coupled GABA-benzodiazepine recognition sites at the GABA(A) receptor.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Cytotoxic action of lindane in neocortical GABAergic neurons is primarily mediated by interaction with flunitrazepam-sensitive GABAA receptors

Vale

Damgaard²,

Suñol

et al. 1998

J. Neurosci. Res.

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“…The convulsant properties of lindane and related pesticides (endosulfan and dieldrin) in acute high dosages have been well established, and this action has been tied to effects on GABAergic inhibitory function in the CNS. [51][52][53][54][55][56][57][58][59] In rat brain, lindane binds to the t-[ 35 S]butylbicyclophosphorothionate (TBPS) site on the GABA receptor/ionophore complex and blocks GABA-mediated chloride flux. [51][52][53][54][55][56] In den- tate gyrus, field potential recordings in intact animals, lindane increases population spike amplitude at dosages well below electrographic seizure threshold (FIG.…”

Section: How Could This State Of Hyperexcitability Come About?mentioning

confidence: 99%

Does the Kindling Model of Epilepsy Contribute to Our Understanding of Multiple Chemical Sensitivity?

Gilbert

2001

Annals of the New York Academy of Sciences

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Multiple chemical sensitivity (MCS) is a phenomenon whereby individuals report an increased sensitivity to low levels of chemicals in the environment. Kindling is a model of synaptic plasticity whereby repeated low‐level electrical stimulation to a number of brain sites leads to permanent increases in seizure susceptibility. Stimulation that is initially subthreshold for subclinical seizure provocation comes, over time, to elicit full‐blown motor seizures. Kindling can also be induced by chemical stimulation, and repeated exposures to some pesticides have been shown to induce signs of behavioral seizure, facilitate subsequent electrical kindling, and induce subclinical electrographic signs of hyperexcitability in the amygdala. Many of the symptoms of MCS suggest that CNS limbic pathways involved in anxiety are altered in individuals reporting MCS. Limbic structures are among the most susceptible to kindling‐induced seizures, and persistent cognitive and emotional sequelae have been associated with temporal lobe epilepsy (TLE) in humans and kindling in animals. Thus, a number of parallels exist between kindling and MCS phenomena, leading to initial speculations that MCS may occur via a kindling‐like mechanism. However, kindling requires the activation of electrographic seizure discharge and has thus been primarily examined as a model for TLE. Events leading to the initial evocation of a subclinical electrographic seizure have been much less well studied. It is perhaps these events that may serve as a more appropriate model for the enhanced chemical responsiveness characteristic of MCS. Alternatively, kindling may be useful as a tool to selectively increase sensitivity in subcomponents of the neural fear circuit to address questions relating the role of anxiety in the development and expression of MCS.

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“…This action may be related to GABAergic neurotransmission since lindane has been shown to affect the picrotoxinin (PTX) binding site associated with the chloride channel of the GABA, receptor complex (Lawrence and Casida, 1984;Abalis et al, 1985;Eldefrawi and Eldefrawi, 1987;Llorens et al, 1990;PomCs et al, 1993). Whether this may also directly involve an action on the GABA and benzodiazepine recognition sites is less clear since lindane does not inhibit binding of [3H]GABA or [3H]flunitrazepam (Cattabeni et al, 1983;Abalis et al, 1985). However, administration of lindane to rats has been shown to result in an increased number of flunitrazepam binding sites and a decreased number of muscimol binding sites in the brain (Soh et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Lindane cytotoxicity in cultured neocortical neurons is ameliorated by GABA and flunitrazepam

Pomés

Frandsen²,

Suñol³

et al. 1994

J of Neuroscience Research

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The effect of lindane (gamma-hexachlorocyclohexane) on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding and GABA-stimulated 36Cl- influx was investigated in cultured cerebral cortical neurons. In addition, the cytotoxic action of lindane as well as a protection by GABA and flunitrazepam were studied together with the ability of lindane to increase the intracellular concentration of free Ca2+. Lindane was found to be toxic to the neurons, an effect that could be completely prevented by the simultaneous presence of GABA (0.1 microM) and flunitrazepam (100 microM) and reduced by GABA alone. An interaction with the GABA receptor-gated chloride channel was demonstrated by an inhibitory action of lindane on [35S]TBPS binding (IC50 188 +/- 51 nM) and on GABA-stimulated 36Cl- influx in the neurons. Lindane only marginally increased the intracellular Ca2+ concentration in the neurons. It is concluded that the cytotoxic action of lindane is mediated through interaction with GABA receptors in a manner essentially independent of changes in intracellular Ca2+ homeostasis.

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Convulsions Induced by Lindane and the Involvement of the GABAergic System

Cited by 18 publications

References 9 publications

Cytotoxic action of lindane in neocortical GABAergic neurons is primarily mediated by interaction with flunitrazepam-sensitive GABAA receptors

Cytotoxic action of lindane in neocortical GABAergic neurons is primarily mediated by interaction with flunitrazepam-sensitive GABAA receptors

Does the Kindling Model of Epilepsy Contribute to Our Understanding of Multiple Chemical Sensitivity?

Lindane cytotoxicity in cultured neocortical neurons is ameliorated by GABA and flunitrazepam

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