Lindane cytotoxicity in cultured neocortical neurons is ameliorated by GABA and flunitrazepam.
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.
Pomés
A
A
Department of Neurochemistry, Consejo Superior de Investigaciones Scientificas, Barcelona, Spain.
Frandsen
A
A
Suñol
C
C
Sanfeliu
C
C
Rodríguez-Farré
E
E
Schousboe
A
A
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D002713:Chlorine / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology*; D001556:Hexachlorocyclohexane / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D018079:Receptors, GABA / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D003292:Convulsants; D018079:Receptors, GABA; D002713:Chlorine; D005680:gamma-Aminobutyric Acid; D001556:Hexachlorocyclohexane; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D011188:Potassium; D002118:Calcium