Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure

Abstract

Background: There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels. However, very few studies have evaluated whether chelation improves cognitive outcomes in Pb-exposed children, or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure.

Objectives: The present study was designed to answer these questions, using a rodent model of early childhood Pb exposure and treatment with succimer, a widely used chelating agent for the treatment of Pb poisoning.

Results: Pb exposure produced lasting impairments in learning, attention, inhibitory control, and arousal regulation, paralleling the areas of dysfunction seen in Pb-exposed children. Succimer treatment of the Pb-exposed rats significantly improved learning, attention, and arousal regulation, although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit. In contrast, succimer treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen.

Conclusions: These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure. These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals.

Figure 1

Succimer treatment of the High-Pb rats was either ineffective or only partially effective in alleviating the impairments in learning, inhibitory control, and early-session attentional function. Percent premature responses in attention task 1 as a function of (A) the duration of the pre-cue delay (averaged across the 20 sessions) and (B) stage of testing (averaged across the pre-cue delay). (C) Percent premature responses in the sustained attention task as a function of the duration of the delay between trial onset and cue presentation. (D) Percent omission errors committed during the first block of trials in each session (trials 1–66) in the sustained attention task as a function of cue duration (slopes for High-Pb vs. control; p = 0.009). Data points are means ± SEs. *p ≤ 0.07. **p < 0.05. ^#p ≤ 0.01.

Figure 2

Heightened reactivity to errors of the High-Pb rats was completely normalized by succimer treatment. (A) The percentage of trials in attention task 1 for which the latency to enter the testing alcove at trial onset was very short (< 0.1 sec) across the 4 blocks of sessions (20 sessions). (B) Percent omission errors for trials following an error in the sustained attention task, plotted as a function of the block of trials within each 200-trial testing session (averaged across the 10 sessions). Data points are means ± SEs. *p < 0.01, High-Pb vs. control. **p < 0.01, High-Pb–succimer vs. High-Pb.

Figure 3

Succimer treatment significantly improved learning ability of the Mod-Pb rats. (A) Visual discrimination task (Mod-Pb–succimer vs. Mod-Pb; main effect contrast, p = 0.03). (B) Attention task 1. Data points are means ± SEs. *p = 0.056; **p ≤ 0.03; ^#p < 0.01, Mod-Pb vs. control. ^##p = 0.03; †p = 0.006, Mod-Pb–succimer vs. Mod-Pb.

Figure 4

Succimer treatment of the non-Pb–exposed rats impaired performance in (A) visual discrimination task (main effect contrast, p = 0.04), (B) attention task 1, and (C) the sustained attention task (treatment × cue duration, p = 0.004). Data points are means ± SEs. *p = 0.07; **p < 0.05, succimer-only vs. controls.

Figure 5

Succimer treatment of the non-Pb-exposed rats impaired performance in the selective attention task. Percent inaccurate responses in the selective attention task, as a function of whether or not a dis-tractor was presented on the current trial and whether the prior trial was correct (A) or incorrect (B). (C) Percent inaccurate responses in the selective attention task, plotted as a function of cue duration. (D) Percent inaccurate responses in the baseline task and the nondistraction trials of the selective attention task (see text). Data shown are means ± SEs. *p = 0.02; **p < 0.01, succimer-only vs. controls.