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TOXICOLOGY

Reversal of Lead-Induced Neuronal Apoptosis by Chelation Treatment in Rats: Role of Reactive Oxygen Species and Intracellular Ca²⁺

Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Gwalior, India

Lead, a ubiquitous and potent neurotoxicant causes several neurophysiological and behavioral alterations. Toxic properties of lead have been attributed to its capability to mimic calcium and alter calcium homeostasis. In this study, we have addressed the following issues: 1) whether chelation therapy could circumvent the altered Ca²⁺ homeostasis and prevent neuronal death in chronic lead-intoxicated rats, 2) whether chelation therapy could revert altered biochemical and behavioral changes, 3) whether combinational therapy using two different chelating agents was more advantageous over monotherapy in lead-treated rats, and 4) what could be the mechanism of neuronal apoptosis. Results indicated that lead caused a significant increase in reactive oxygen species, neuronal nitric-oxide synthetase, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and altered bcl₂/bax ratio indicated mitochondrial-dependent apoptosis. Most of these alterations reverted toward normal level following combination therapy over monotherapy with calcium disodium EDTA (CaNa₂EDTA) or monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA). It could be concluded from our present results that combined therapy with CaNa₂EDTA and MiADMSA might be a better treatment protocol than monotherapy with these chelators in lead-induced neurological disorders. We for the first time report the role of Ca²⁺ in regulating neurological dystrophy caused by chronic lead exposure in rats and its recovery with a two-course treatment regime of mono or combination therapy.

Address correspondence to: Dr. Swaran Jeet Singh Flora, Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Rd., Gwalior 474 002, India. E-mail: sjsflora{at}hotmail.com

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