Vidhu Pachauri

Chelation in metal intoxication.

Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.

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.

Arsenic induced neuronal apoptosis in guinea pigs is Ca2+ dependent and abrogated by chelation therapy: role of voltage gated calcium channels.

Arsenic contaminated drinking water has affected more than 200 million people globally. Chronic arsenicism has also been associated with numerous neurological diseases. One of the prime mechanisms postulated for arsenic toxicity is reactive oxygen species (ROS) mediated oxidative stress. In this study, we explored the kinetic relationship of ROS with calcium and attempted to dissect the calcium ion channels responsible for calcium imbalance after arsenic exposure. We also explored if mono- or combinational chelation therapy prevents arsenic-induced (25ppm in drinking water for 4 months) neuronal apoptosis in a guinea pig animal model. Results indicate that chronic arsenic exposure caused a significant increase in ROS followed by NO and calcium influx. This calcium influx is mainly dependent on L-type voltage gated channels that disrupt mitochondrial membrane potential, increase bax/bcl2 levels and caspase 3 activity leading to apoptosis. Interestingly, blocking of ROS could completely reduce calcium influx whereas calcium blockage partially reduced ROS increase. While in general mono- and combinational chelation therapies were effective in reversing arsenic induced alteration, combinational therapy of DMSA and MiADMSA was most effective. Our results provide evidence for the role of L-type calcium channels in regulating arsenic-induced calcium influx and DMSA+MiADMSA combinational therapy may be a better protocol than monotherapy in mitigating chronic arsenicosis.

Monoisoamyl 2, 3‐Dimercaptosuccinic Acid (MiADMSA) Demonstrates Higher Efficacy by Oral Route in Reversing Arsenic Toxicity: A Pharmacokinetic Approach

Monoisoamyl DMSA (MiADMSA), a lipophilic chelating agent has emerged as a promising drug for the treatment of arsenic. The present study aimed at exploring the optimum dose and route of administration for achieving maximum arsenic elimination with minimal side effects. We also carried out a pharmacokinetic analysis of this drug to support arsenic chelation. Rats were exposed to arsenic (25 ppm) for 6 months and later received MiADMSA (50 or 100 mg/kg) orally and via i.p. route for 5 days. Oxidative stress parameters and arsenic levels in soft tissues, liver function test and histopathology of liver and kidney were performed. Plasma kinetic of MiADMSA (plasma-free drug and total drug) at 50 and 100 mg/kg p.o. was carried out. Arsenic exposure resulted in significant oxidative stress and hepatotoxicity. MiADMSA at 50 mg/kg dose administered orally provided about 45% and 75% protection against oxidative stress and in lowering body arsenic burden, respectively, against 25% and 40% via i.p. route. Pharmacokinetic analysis supported prolonged availability of the drug through oral administration. Collectively, these findings led us to conclude that oral administration of MiADMSA was more effective than intraperitoneal administration and that the minimum effective dose with least side effects was 50 mg/kg.

Co-administration of meso 2,3-dimercaptosuccinic acid monoesters reduces arsenic concentration and oxidative stress in gallium arsenide exposed rats.

1. Gallium arsenide (GaAs), a semiconductor, exerts toxicity as a result of its constitutive moieties; that is, gallium and arsenic that becomes dissociated after exposure. The present study focuses on reducing arsenic concentration from the target organs using monoesters of meso 2,3‐dimercaptosuccinic acid (DMSA) either individually or in combination.

Moringa (Moringa oleifera) Seed Extract and the Prevention of Oxidative Stress

Publisher Summary This chapter examines the nutritional content of moringa seed extracts and its utility in the prevention of various diseases. Ayurveda and the Chinese ancient medicinal system, among others, are known for their exhaustive experience in herbal remediation. Moringa oleifera is one plant used in these ancient systems. The seed extracts are rich sources of a number of vitamins and minerals, which may contribute significantly to its antioxidant, therapeutic, and nutritional values. These beneficial effects are both direct and indirect and may be attributed to high concentrations of methionine, cysteine, and antioxidants such as vitamins C and E and β-carotene. It also provides protection against toxic metal induced oxidative stress by virtue of its chelation and antioxidant properties. The high phenolic content, ascorbic acid, and isothiocynate derivatives in Moringa oleifera seed extract contribute to protection against inflammatory diseases, directly or indirectly. A significant recovery in blood and liver enzymatic and non-enzymatic oxidative stress markers suggests a dual mechanism whereby the seeds, by lowering the arsenic burden, indirectly reduces arsenic-induced oxidative stress while executing direct free radical scavenging and antioxidant-enhancing mechanisms. The cancer-preventive effects of Moringa oleifera seed extract relate to its activity in modulating biotransformation enzymes to facilitate detoxification. The seed extract shows pronounced antimicrobial and hepatoprotective potential.

Monensin potentiates lead chelation efficacy of MiADMSA in rat brain post chronic lead exposure.

The present study evaluates combination therapy with a chelating agent, MiADMSA and a Na(+) ionophore, monensin against sub-chronic lead toxicity in rats. Animals were exposed to 0.1% lead in drinking water for 16 weeks and then treated with either MiADMSA at 50mg/kg body weight, or monensin at 10mg/kg, or both in combination for a period of 5 days was administered. Biomarkers indicative of oxidative stress like ROS, GSH, GSSG and TBARS demonstrated lead-induced toxic manifestations in blood, kidney and brain. Antioxidants like SOD, catalase and glutathione peroxidase along with specific lead biomarker, blood ALAD were also severely depleted in lead intoxicated animals. Serum parameters and histopathological findings supported the said results. MiADMSA treatment during both mono- and combination therapy with monensin, restored the antioxidant status and recovered biochemical and haematological variables due to lead. However, monensin alone was not found to be effective in the given scenario. Interestingly, combination therapy in its ability to revert lead-induced overall systemic toxicity was only found at par with the MiADMSA monotherapy except for its chelation potential. Monensin given in combination with MiADMSA potentiated its lead chelation ability especially from brain, along with maintaining the normal copper concentrations in the organ unlike MiADMSA monotherapy.