Geetu Saxena

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

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.

Environmental occurrence, health effects and management of lead poisoning

Publisher Summary This chapter discusses the environmental occurrence, health effects and management of lead poisoning. Lead poisoning is an old and a significant public-health problem throughout the world. Although the incidence of occupational and adult lead poisoning has declined in the recent past, the problem still exists. It often goes unrecognized for long periods because of the low index of suspicion compounded by incomplete surveillance of the risk population. Toxicity correlates with lead concentration in blood and progresses from biochemical and subclinical abnormalities, at levels around 10 μg/dL, to coma and to death at levels more than 100 μg/dL. Blood lead levels below 70 μg/dL can result in damage to the central nervous system, kidneys, and the hematopoietic system. Lead toxicity is also associated with a two to three point decrease in IQ test scores for every increase in 10 μg/dL in the lead level in blood. Elevated blood lead is also associated with neurodevelopment abnormalities—including attention-deficit disorders, behavioral disturbances, learning disabilities and deficits in fine and gross development.

Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, 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 DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

Arsenic, Cadmium, and Lead

Publisher Summary This chapter discusses the toxic effects of conventionally known metals such as lead, arsenic and mercury on the reproductive system and developmental processes. The chapter comprises a mechanistic understanding of these toxicities with respect to the toxicokinetics of the metal and related risk assessment. Metal toxicity has been documented as one of the prime mass toxicants especially in the case of occupational and environmental hazards. Metals may cause a wide spectrum of reproductive and developmental adverse effects such as reduced fertility, abortions, retarded growth at the intrauterine cavity, skeletal deformities, malformations and retarded development especially of the nervous system. Any teratogen is known to produce toxic manifestations in small doses either directly or injury mediated via systemic toxicity mostly by virtue of high-dose effect. The important mechanisms of action of arsenic are placental transfer, oxidative stress, direct binding with thiol group etc. The toxicity of arsenic in male and female reproductive organs is also explained. It also throws some light on the therapeutic strategies for metal toxicity. The chapter concludes that the advent of awareness towards environmental, occupational and lifestyle exposure to metals and reports revealing their toxic potential and mechanism is mainly responsible for increasing investigations into their reproductive and developmental effects.

Changes in brain biogenic amines and haem biosynthesis and their response to combined administration of succimers and Centella asiatica in lead poisoned rats

This study was designed to investigate the therapeutic potential of meso 2,3‐dimercaptosuccinic acid (DMSA) and one of its monoesters, monoisoamyl DMSA (MiADMSA), individually or when administered in combination with an extract of Centella asiatica against experimental lead intoxication in rats. Biochemical variables indicative of alterations in the central nervous system and haem biosynthesis were investigated to determine the toxicity in male Wistar rats. Thirty five rats were exposed to 0.2% lead acetate for 10 weeks, followed by 10 days of treatment with DMSA and MiADMSA (50 mg kg−1, i.p., once daily) alone and in combination with C. asiatica (200 mg kg−1, p.o., once daily). Biochemical variables indicative of oxidative stress and brain biogenic amines, along with lead concentration in blood and brain, were measured. Lead exposure caused a significant depletion of blood and brain δ‐aminolevulinic acid dehydratase (ALAD) activity, an important enzyme of the haem biosynthesis pathway, and glutathione (GSH) level. These changes were accompanied by a marked increase in reactive oxygen species (ROS) level, thiobarbituric acid reactive substances (TBARS), δ‐aminolevulinic acid synthase (ALAS) and oxidized glutathione (GSSG) activity in blood and brain. Significant depletion of brain noradrenaline (norepinephrine, NE), 5‐hydroxytryptamine (5‐HT), dopamine (DA) and acetylcholinesterase (AChE) also were observed following lead exposure. Also seen was a significant depletion in brain glutathione peroxidase (GPx), glutathione S‐transferase (GST) and monoamine oxidase activity, as well as blood and brain superoxide dismutase (SOD) activity. These biochemical changes were correlated with an increased uptake of lead in blood and brain. Combined administration of MiADMSA and C. asiatica was most effective in reducing these alterations, including biogenic amines, besides reducing body lead burden, compared with individual treatment with MiADMSA. Certain other biochemical variables responded favourably to combination therapy and monotherapy with MiADMSA. Thus, supplementation of C. asiatica during chelation could be recommended for achieving optimum effects of chelation therapy.

Arsenicals: Toxicity, their Use as Chemical Warfare Agents, and Possible Remedial Measures

Arsenic is used in industries and agricultural production, and it also appears in the food chain. Although information about arsenic and its inorganic and organic derivatives is now widely reported, there is very little information about their use as chemical warfare agents. The use of arsenicals remains a potential threat because they are relatively easy to manufacture and may cause significant morbidity and mortality. Knowledge about these arsenicals is important for planning a response in an emergency.