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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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Arsenicosis, due to contaminated drinking water, is a serious health hazard in terms of morbidity and mortality. Arsenic induced free radicals generated are known to cause cellular apoptosis through mitochondrial driven pathway. In the present study, we investigated the effect of arsenic interactions with various complexes of the electron transport chain and attempted to evaluate if there was any complex preference of arsenic that could trigger apoptosis. We also evaluated if chelation with monoisoamyl dimercaptosuccinic acid (MiADMSA) could reverse these detrimental effects. Our results indicate that arsenic exposure induced free radical generation in rat neuronal cells, which diminished mitochondrial potential and enzyme activities of all the complexes of the electron transport chain. Moreover, these complexes showed differential responses towards arsenic. These early events along with diminished ATP levels could be co-related with the later events of cytosolic migration of cytochrome c, altered bax/bcl(2) ratio, and increased caspase 3 activity. Although MiADMSA could reverse most of these arsenic-induced altered variables to various extents, DNA damage remained unaffected. Our study for the first time demonstrates the differential effect of arsenic on the complexes leading to deficits in bioenergetics leading to apoptosis in rat brain. However, more in depth studies are warranted for better understanding of arsenic interactions with the mitochondria., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Gallium arsenide (GaAs), an intermetallic semiconductor finds widespread applications in high frequency microwave and millimeter wave, and ultra fast supercomputers. Extensive use of GaAs has led to increased exposure to humans working in semiconductor industry. GaAs has the ability to dissociate into its constitutive moieties at physiological pH and might be responsible for the oxidative stress. The present study was aimed at evaluating, the principle moiety (Ga or As) in GaAs to cause neurological dysfunction based on its ability to cause apoptosis, in vivo and in vitro and if this neuronal dysfunction translated to neurobehavioral changes in chronically exposed rats. Result indicated that arsenic moiety in GaAs was mainly responsible for causing oxidative stress via increased reactive oxygen species (ROS) and nitric oxide (NO) generation, both in vitro and in vivo. Increased ROS further caused apoptosis via mitochondrial driven pathway. Effects of oxidative stress were also confirmed based on alterations in antioxidant enzymes, GPx, GST and SOD in rat brain. We noted that ROS induced oxidative stress caused changes in the brain neurotransmitter levels, Acetylcholinesterase and nitric oxide synthase, leading to loss of memory and learning in rats. The study demonstrates for the first time that the slow release of arsenic moiety from GaAs is mainly responsible for oxidative stress induced apoptosis in neuronal cells causing behavioral changes.

Garlic is well known as a folk remedy for a variety of ailments since ancient times, however, very few studies are available suggesting its beneficial role against arsenic toxicity pertaining to its ability to eliminate arsenic from the blood and soft tissues and in reversal of arsenic-induced oxidative stress in affected tissues. The present study was planned to investigate the protective efficacy of aqueous garlic extract using two different doses on parameters suggestive of hepatic injury, tissue oxidative stress and mobilization of arsenic. Further, an attempt to understand the mechanism of arsenic in inducing hepatic apoptosis was also studied. Results of the present study suggested that arsenic administration in mice caused generation of reactive oxygen species (ROS) causing apoptosis through mitochondria-mediated pathway. The ROS generation in hepatic tissue reverted to normal values after co-administration of garlic extracts. The study provides significant evidence that garlic extracts contain strong anti-oxidant property which could be beneficial in preventing arsenic-induced toxicity in cells. However, further research is required to determine whether the results from animal studies are applicable to humans before garlic can be recommended as a putative agent against arsenic toxicity.

Arsenicosis, due to contaminated drinking water in the Indo-Bangladesh region, is a serious health hazard in terms of morbidity and mortality. Reactive oxygen species (ROS) generated due to arsenic toxicity have been attributed as one of the initial signals that impart cellular toxicity, which is controlled by the internal antioxidant glutathione (GSH). In the present study, we investigated (i) the role of GSH and its linked enzymes, glutathione peroxidase and glutathione reductase, in reversing chronic arsenic toxicity using a thiol chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), or one of its analogues individually or in combination; (ii) if alterations in the carbon side chain of DMSA increased efficacy; and (iii) whether the combination therapy enhance arsenic removal from hepatic tissue and prevent hepatic apoptosis. Results indicated that chronic arsenic exposure led to a ROS-mediated, mitochondrial-driven, caspase-dependent apoptosis in hepatic cells with a significant increase in glutathione disulfide (GSSG) levels and decreased glutathione reductase levels. Monotherapy with DMSA and its analogues did show minimal recovery postchelation. However, the combination of DMSA with long carbon chain analogues like monoisoamyl DMSA (MiADMSA) or monocyclohexyl DMSA (MchDMSA) showed a better efficacy in terms of reducing the arsenic burden as well as reversing altered biochemical variables indicative of oxidative stress and apoptosis. We also observed that GSH and its linked enzymes, especially glutathione reductase, play a vital role in scavenging ROS, maintaining GSH pools, and providing clinical recoveries. On the basis of the above observations, we recommend that combinational therapy of DMSA and its long carbon chain analogues MiADMSA or MchDMSA would be more effective in arsenic toxicity.

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.

The present study reports the biological activity of 8-methyl-4-(3-diethylamino-propylamino) pyrimido [4';5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivative structurally related to ellipticine and suggests a possible mechanism through which the compound induces apoptosis in carcinoma cell lines. Out of the 8 cell lines used in the study as representatives of different types of cancer, MDPTQ was found to be effective only against leukemia cell lines (HL-60 and K-562) whereas it had no effect on normal human bone marrow cells (BMC) which were used as controls. Fall mitochondrial membrane potential and increased reactive oxygen species (ROS) were mainly responsible for inducing apoptosis in the two cell lines. Cell death was demonstrated by increase in caspase 3 activity as well as phosphatidyl serine exposure. Pre-incubation with N-acetylcysteine (NAC) reduced the increased ROS and caspase 3 activity as well as phosphatidyl serine exposure. MDPTQ also caused cell cycle arrest in these cell lines. The above study for the first time reports the mode of action of a quinoline derivative, which could be a possible future candidate for leukemia therapy. However, there are lot of questions that need to be answered in terms of signalling pathways and its effects on animal models.

Abstract: 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. [Copyright &y& Elsevier]

Abstract: There is growing evidence that metalloid-induced cell death in protozoan parasites is due to oxidative injury; however, the biochemical changes related to this event are not fully understood. Leishmania spp. demonstrated cross-resistance to two related metalloids, arsenic and antimony, and both metalloids induced cell death accompanied by cell shrinkage and DNA fragmentation that was preceded by an increase in reactive oxygen species. Both drugs caused mitochondrial dysfunction in terms of loss of membrane potential and a drop in ATP levels. Arsenic treatment resulted in an elevation of intracellular Ca2+ levels that did not occur with antimony exposure. Cellular glutathione level was reduced after antimony treatment but arsenic did not affect glutathione. Inhibition of Ca2+ influx during arsenic treatment reduced cell death, whereas supplementation of glutathione during antimony treatment rescued cell loss. Under iron-depleted conditions, the cytotoxic effects of arsenic and antimony did not occur and cell survival increased; in contrast, the presence of excess iron resulted in higher cell death. Therefore, this study provides a new possibility that iron can potentiate parasite death induced by metalloids like arsenic and antimony. In addition, an important observation is that the two similar metalloids produce toxicity by very different mechanisms. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Metal intoxication particularly neurotoxicity, genotoxicity, or carcinogenicity is widely known. This review summarizes our current understanding about the mechanism by which metalloids or heavy metals (particularly arsenic, lead, cadmium and mercury) induce their toxic effects. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. The toxic manifestations of these metals are caused primarily due to imbalance between pro-oxidant and antioxidant homeostasis which is termed as oxidative stress. Besides these metals have high affinity, for thiol groups containing enzymes and proteins, which are responsible for normal cellular defense mechanism. Long term exposure to these metals could lead to apoptosis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases and transcription factors. Chelation therapy with chelating agents like calcium disodium ethylenediamine tetra acetic acid (CaNa2EDTA), British Anti Lewisite (BAL), sodium 2,3- dimercaptopropane 1-sulfonate (DMPS), meso 2,3-dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against metal poisoning. Despite many years of research we are still far away from effective treatment against toxicity caused due to exposure to heavy metals/metalloids. The treatment with these chelating agents is compromised with number of serious side-effects. Studies show that supplementation of antioxidants along-with a chelating agent prove to be a better treatment regimen than monotherapy with chelating agents. This review attempts a comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/ free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects. We have selected only arsenic, lead, mercury and cadmium for this article keeping in view current concerns and literature available. [ABSTRACT FROM AUTHOR]