Investigations into the mechanism of 2,3-dimercaptopropanol neurotoxicity.
2,3 dimercaptopropanol (BAL), is a dithiol chelating agent, used for the treatment of heavy metal intoxication; however, this compound has low therapeutic efficacy and in some situations may cause neurotoxic effects. In experimental models, administration of high doses of BAL produces seizures that culminate in animal death. However, investigations on the modulation of neurotransmitter system(s) involved in BAL-induced seizures are still lacking in the literature. In the present study, the neurotoxicity of BAL, as measured by the manifestation of seizures was examined and the modulation of glutamatergic and GABAergic receptors and ion channels potentially involved in BAL-induced seizures was investigated. The results demonstrated that BAL (18.6 mg/kg) induced seizures and all mice died within one day. GABAergic allosteric modulators (3 or 12 mg/kg diazepam and 50 mg/kg phenobarbital) blocked the appearance of seizure and reduced almost completely the death caused by BAL. Carbamazepine (5 mg/kg) significantly reduced the incidence of BAL-induced seizures, while sodium valproate and MK-801 were not effective in reducing the incidence of seizures. Valproate (300 mg/kg) and MK-801(0.5 mg/kg) prolonged the latencies for onset of seizures; however, all animals died within one day after BAL administration. High doses of ZnCl2 (135 mg/kg) blocked the appearance of seizures episodes, but no animal survived more than one day. The content of total non-protein -SH in brain of mice treated with 18.6 and 124 mg/kg BAL increased from 0.9+/-0.3 nmol/g (control animals) to 1.7+/-0.3 and 3.5+/-0.8 nmol/g, respectively. In vitro, 0.1-1 mM concentrations of BAL inhibited [3H]glutamate and [3H]MK-801 binding, but increased the binding of [3H]muscimol to brain synaptic plasma membrane. The results reported here demonstrate that GABAergic allosteric modulators (diazepam and phenobarbital) and carbamazepine, a compound that acts by prolonging the recovery of voltage-activated ion channels from inactivation, are able to abolish BAL-induced seizures, while the NMDA antagonist (MK-801) prolonged the latencies for onset of seizures suggesting that modulators of this subtype of glutamate receptor have a modest role on BAL-induced seizures. The results of the present study suggest that allosteric modulators of GABAergic system and carbamazepine, a voltage-gated Na+-channel antagonist, should be considered for the treatment of animals or patients intoxicated with BAL.
Nogueira
C W
CW
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, RS, Brasil. cnp@zaz.com.br
Soares
F A
FA
Bolzan
R C
RC
Jacques-Silva
M C
MC
Souza
D O
DO
Rocha
J B
JB
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D004112:Dimercaprol / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000927:Anticonvulsants; D002614:Chelating Agents; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013438:Sulfhydryl Compounds; D004112:Dimercaprol; D018698:Glutamic Acid; D016291:Dizocilpine Maleate