Efficacy of succimer chelation for reducing brain Pb levels in a rodent model.
Efficacy of succimer chelation for reducing brain Pb levels in a rodent model.
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琥珀酸螯合剂在啮齿动物模型中降低脑铅水平的功效。
DOI：
10.1006/enrs.1998.3854
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Strupp,BJ
中科院分区：
文献类型：
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作者：
Smith,D;Bayer,L;Strupp,BJ
越来越多的证据表明，早期低水平铅（Pb）暴露会导致儿童持久的认知障碍，这强调了开发改进的治疗干预的必要性。虽然螯合剂已被证明可以有效地降低体内铅水平，但尚不清楚这种治疗是否能改善铅诱导的认知功能障碍。尽管脑铅水平是与神经认知结果最相关的暴露参数，但由于需要依赖血铅水平的降低作为治疗效果的指标，这一领域的临床研究受到阻碍。目前的研究旨在提供信息，将有助于未来在这一领域的研究在人类和动物模型。这些研究的目的是（1）评价不同剂量和持续时间的琥珀酰（内消旋-2，3-二巯基琥珀酸; DMSA）螯合降低脑和血铅水平的有效性和（2）确定血铅在螯合后可作为脑铅替代物的程度。Long-Evans连帽大鼠从出生到生命第31天（研究1）或第40天（研究2）暴露于铅，然后口服溶剂或两种琥珀酰二氢吡啶方案之一，持续7天或21天。结果表明，7天的琥珀酰亚胺治疗产生了1.5- 2.5倍的减少铅在血液中比在大脑中，相对于时间匹配的车辆组。延长的治疗（21）天没有进一步降低血液Pb水平（相对于7天琥珀酰亚胺治疗），但与时间匹配的载体组相比，确实产生了脑Pb水平的进一步降低.因此，螯合介导的减少脑铅没有平行减少血铅在治疗过程中。虽然这些数据与人类的相关性可能会混淆啮齿类动物和灵长类动物之间的解剖和生理差异，以及琥珀酰亚胺（DMSA）代谢的差异，他们建议，临床研究应谨慎使用血铅作为螯合治疗降低脑铅水平的疗效指标。
Increasing evidence indicates that early low-level lead (Pb) exposure produces enduring cognitive impairment in children, underscoring the need to develop improved therapeutic intervention. Although chelating agents have been shown to effectively reduce body Pb levels, it is not yet known whether this treatment ameliorates Pb-induced cognitive dysfunction. Clinical research in this area is hampered by the need to rely on reductions in blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greatest relevance to neurocognitive outcomes. The present studies were designed to provide information that will aid future research in this area in both human and animal models. The objectives of these studies were (1) to evaluate the efficacy of different doses and durations of succimer (meso-2,3-dimercaptosuccinic acid; DMSA) chealtion for reducing brain and blood Pb levels and (2) to determine the extent to which blood Pb can serve as a surrogate of brain Pb following chelation. Long–Evans 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 vehicle or one of two succimer regimens for a duration of either 7 or 21 days. 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 time- matched vehicle groups. Thus, chelation-mediated reductions in brain Pb did not parallel reductions in blood Pb over the course of treatment. While the relevance of these data to humans may be confounded by anatomical and physiological differences between rodents and primates, as well as differences in the metabolism of succimer (DMSA), they suggest that clinical studies should exercise caution when using blood Pb as an index of the efficacy of chelation tratment for reducing brain Pb levels.