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

Abstract

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 2ϩ 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 2ϩ 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.

The effect of ascorbic acid on mercury-induced changes on the histomorphology of the cerebellum of adult wistar rats

“…From the present observation, it has been shown that there is a direct relationship between the concentration of mercuric chloride, ascorbic acid and the level of neurological damage in the cerebellum.The present study showed that the ascorbic acid administration reduced the damage done to the cerebellum was in agreement with the findings that showed that natural agents rich in antioxidants are involved in the improvement in enzymatic activity and hence in the reduction of oxidative stress (Ahamed and Siddiqui, 2007;Farina et al, 2013). This may play a significant role in the reversion of mercury toxicity by forming inert complexes and inhibiting their toxicity on the dopaminergic neurons (Flora et al, 2007;Jomovaand Volko, 2011). The present study showed a significant increase in the mean SOD levels in the experimental groups and a significant decrease in the LPO mean values when compared to the Control.…”

Protective effect of Etlingera elatior (torch ginger) extract on lead acetate - induced hepatotoxicity in rats

“…These results are in agreement with previous reports (Flora et al, 2007;Newairy and Abdou, 2009). The decrease in GPX level in the liver with lead acetate exposure could be due to lead's displacement of the selenocysteine group from the active site in the liver tissue.…”

“…GST is also neutralizing oxidative molecules like ROS. The significant reduction in GST levels observed after lead acetate exposure could be due to lead acetate affects on sulfhydryl groups as lead is known to be able to bind irreversibly with -SH groups on proteins, rendering them useless (Mudipall, 2007;Flora et al, 2007;Gurer and Ercal, 2000;Hsu and Guo, 2002;Newairy and Abdou, 2009).…”

Elucidation of mechanisms underlying the protective effects of olive leaf extract against lead-induced neurotoxicity in Wistar rats

“…Many authors attribute the neurological symptoms of Pb toxicity to the ability of 5-aminolevulinic acid to inhibit either the K + -stimulated release of γ-aminobutyric acid (GABA) from preloaded rat brain synaptosomes or GABA binding to synaptic membranes (Brennan et al, 1995). Furthermore, it has been observed that Pb increases reactive oxygen species (ROS) levels along with intracellular Ca 2+ elevation which, in turn, evokes a decline of mitochondrial potential with apoptosis via cytochrome c release (Flora et al, 2007b). Xu et al (2006) have shown that Pb elicits DNA damage and apoptosis in PC 12 cell line, accompanied by an increase in the Bax/ Bcl2 ratio and caspase-3 activity.…”