Assuntos
Dimercaprol/administração & dosagem , Succímero/administração & dosagem , Unitiol/administração & dosagem , Ácido Aminolevulínico/antagonistas & inibidores , Ácido Aminolevulínico/química , Animais , Química Encefálica/efeitos dos fármacos , Dimercaprol/farmacocinética , Dimercaprol/toxicidade , Epilepsia Tônico-Clônica/induzido quimicamente , Injeções Subcutâneas , Rim/química , Rim/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Camundongos , Succímero/farmacocinética , Succímero/toxicidade , Compostos de Sulfidrila/química , Fatores de Tempo , Testes de Toxicidade Aguda/métodos , Unitiol/farmacocinética , Unitiol/toxicidade , Zinco/químicaRESUMO
The therapeutic use of BAL (2,3-dimercaptopropanol) as treatment for poisoning has been halted by data suggesting serious neurotoxicity. This article is a report on the effects of BAL and other dithiols, DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid), on [3H]glutamate release and uptake by rat brain synaptosomes and [3H]glutamate uptake by synaptic vesicles. BAL (100 microM) inhibited glutamate uptake (30%) and stimulated its basal release (30%) in synaptosomes, without affecting K+-stimulated release. BAL also inhibited glutamate uptake by synaptic vesicles (up to 60%). DMPS and DMSA (100 microM) had no significant effects on these parameters. The data reported here provide some evidence of glutamate involvement in BAL-induced neurotoxicity by demonstrating direct effects of BAL on glutamatergic system modulation.
Assuntos
Quelantes/toxicidade , Dimercaprol/toxicidade , Ácido Glutâmico/farmacocinética , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Encéfalo/metabolismo , Técnicas In Vitro , Masculino , Potássio/farmacologia , Ratos , Ratos Wistar , Succímero/toxicidade , Trítio , Unitiol/toxicidadeRESUMO
The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.