Effect of dithiol chelating agents on [3H]MK-801 and [3H]glutamate binding to synaptic plasma membranes.

Abstract

2,3-Dimercaptopropanol (BAL- British Anti-Lewesite) is a dithiol chelating agent used for the treatment of heavy metal poisoning, however, BAL can produce neurotoxic effects in a variety of situations. Based on the low therapeutic efficiency of BAL other dithiols were developed and DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid) are becoming used for treatments of humans exposed to heavy metals. In the present investigation the effect of dithiols in the glutamatergic system was examined. The results showed that BAL inhibited [3H]MK-801 and [3H]glutamate binding in a concentration-dependent manner. At 100 microM BAL and DMSA caused a significantly inhibition of [3H]MK-801 binding to brain membranes (p < 0.05 by Duncan's multiple range test). BAL at 100 microM caused an inhibition of 40% on [3H]glutamate binding. DMPS and DMSA had no significant effect on [3H]glutamate binding. Dithiotreitol (DTT), abolished the inhibitory effect of BAL on [3H]MK-801 binding. The protection exerted by DTT suggests that BAL inhibit [3H]MK-801 binding by interacting with cysteinyl residues that are important for redox modulation of receptor responses. ZnCl2 inhibited [3H]glutamate and [3H]MK-801 binding to brain synaptic membrane; nevertheless, the inhibitory effect was slight more accentuated for [3H]MK-801 than [3H]glutamate binding (p < 0.05). The inhibition caused by 10 microM ZnCl2 on [3H]MK-801 binding was attenuated by BAL. The findings present in this study may provide the evidence that BAL affect the glutamatergic system and these effects can contributed to explain, at least in part, why BAL, in contrast to DMPS and DMSA is neurotoxic.