Effect of chelation with meso-dimercaptosuccinic acid (DMSA) before and after the appearance of lead-induced neurotoxicity in the rat.

This paper examines whether a chelating agent (DMSA) can prevent and reverse the effects of lead (Pb) as evidenced by changes in brain glial fibrillary acidic protein (GFAP) concentration and in the habituation pattern of rearing behavior. Male F344 rats (42 days old) received Pb acetate at 150 or 2000 ppm as Pb in their drinking water for 21 days and returned to regular water for another 21 days to observe recovery. Blood Pb (BPb) concentration rose to 37 and 82 microg/dl for 150 and 2000 ppm, respectively. Rats exposed to 150 ppm Pb exhibited changes in GFAP concentration and behavioral hyperactivity, when placed in an unfamiliar cage. The 2000 ppm Pb exposure caused greater changes in GFAP, but behavioral hyperactivity appeared only postexposure, when BPb was declining. Chelation (DMSA, 50 mg/kg po, 3 times/week for 21 days) decreased the BPb concentration, and prevented and reversed the Pb-induced changes in GFAP and rearing, but not in body weight. Administration of DMSA by itself for 21 days caused no untoward effects in brain GFAP, behavior, or body weight. Concurrent administration of DMSA and Pb resulted in no evidence of additive toxicity. Results indicate that: (1) A brief behavioral test of habituation is a sensitive index of neurotoxicity and chelating therapy; (2) Pb-induced hyperactivity depends upon BPb concentration regardless of whether activity is measured during or after exposure; (3) repeated treatment with DMSA is effective in reducing Pb neurotoxicity; (4) there was no evidence that DMSA enhanced the absorption of Pb. The finding that DMSA administered late in exposure can hasten the recovery of toxic signs suggests that extracellular Pb continues to play a significant role even after toxic signs have appeared.