EFFICACY OF SUCCIMER CHELATION FOR REDUCING BRAIN PB LEVELS IN A RODENT MODEL

Increasing evidence indicates that early low-level lead (Pb) exposure produces enduring cognitive impairment in children, underscoring the n eed to develop improved therapeutic intervention. Although chelating a gents have been shown to effectively reduce body Pb levels, it is not yet known whether this treatment ameliorates Ph-induced cognitive dysf unction. Clinical research in this area is hampered by the need to rel y on reductions in blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of gre atest relevance to neurocognitive outcomes. The present studies were d esigned to provide information that will aid future research in this a rea in both human and animal models. The objectives of these studies w ere (1) to evaluate the efficacy of different doses and durations of s uccimer (meso-2,3-dimercaptosuccinic acid; DMSA) chealtion for reducin g brain and blood Pb levels and (2) to determine the extent to which b lood Pb can serve as a surrogate of brain Pb following chelation. Long -Evens hooded rats were exposed to Pb from birth until day 31 (Study 1 ) or day 40 (Study 2) of life, followed by oral treatment with a vehic le or one of two succimer regimens for a duration of either 7 or 21 da ys. Results indicated that 7 days of succimer treatment produced a 1.5 - to 2.5-fold greater reduction of Pb in blood than in brain, relative to time-matched vehicle groups. Prolonged treatment (21) days did not further reduce blood Pb levels (relative to 7 day succimer treatment) , but did produce further reductions in brain Pb level compared to tim e-matched vehicle groups. Thus, chelation-mediated reductions in brain Pb did not parallel reductions in blood Pb over the course of treatme nt. While the relevance of these data to humans may be confounded by a natomical and physiological differences between rodents and primates, as well as differences in the metabolism of succimer (DMSA), they sugg est that clinical studies should exercise caution when using blood Pb as an index of the efficacy of chelation tratment for reducing brain P b levels. (C) 1998 Academic Press.