Investigations into the mechanism of 2,3-dimercaptopropanol neurotoxicity

2,3 dimercaptopropanol (BAL), is a dithiol chelating agent, used for the tr eatment of heavy metal intoxication; however, this compound has low therape utic efficacy and in some situations may cause neurotoxic effects. In exper imental models, administration of high doses of BAL produces seizures that culminate in animal death. However, investigations on the modulation of neu rotransmitter system(s) involved in BAL-induced seizures are still lacking in the literature. In the present study, the neurotoxicity of BAL, as measu red by the manifestation of seizures was examined and the modulation of glu tamatergic 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 al losteric modulators (3 or 12 mg/kg diazepam and 50 mg/kg phenobarbital) blo cked the appearance of seizure and reduced almost completely the death caus ed by BAL. Carbamazepine (5 mg/kg) significantly reduced the incidence of B AL-induced seizures, while sodium valproate and MK-801 were not effective i n 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/k g) 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 treate d with 18.6 and 124 mg/kg BAL increased from 0.9 +/- 0.3 nmol/g (control an imals) to 1.7 +/- 0.3 and 3.5 +/- 0.8 nmol/g, respectively. In vitro, 0.1-1 mM concentrations of BAL inhibited [H-3]glutamate and [H-3]MK-801 binding, but increased the binding of [H-3]muscimol to brain synaptic plasma membra ne. The results reported here demonstrate that GABAergic allosteric modulat ors (diazepam and phenobarbital) and carbamazepine, a com pound that acts b y prolonging the recovery of voltage-activated ion channels from inactivati on, are able to abolish BAL-induced seizures, while the NMDA antagonist (MK -801) prolonged the latencies for onset of seizures suggesting that modulat ors of this subtype of glutamate receptor have a modest role on BAL-induced seizures. The results of the present study suggest that al losteric modula tors of GABAergic system and carbamazepine, a voltage-gated Na+-channel ant agonist, should be considered for the treatment of animals or patients into xicated with BAL.