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 Ca(2+) 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 bcl(2)/bax ratio indicated mitochondrial-dependent apoptosis. Most of these alterations reverted toward normal level following combination
therapy over monotherapy with
calcium disodium EDTA (CaNa(2)
EDTA) or monoisoamyl meso-
2,3-dimercaptosuccinic acid (
MiADMSA). It could be concluded from our present results that combined
therapy with CaNa(2)
EDTA 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 Ca(2+) 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.