title: Arsenic induced neuronal apoptosis in guinea pigs is Ca2+ dependent and abrogated by chelation therapy: role of voltage gated calcium channels.
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.
authors: Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India.
authors: Vidhu
authors: V
authors: Pachauri
authors: Ashish
authors: A
authors: Mehta
authors: Deepshikha
authors: D
authors: Mishra
authors: Swaran J S
authors: SJ
authors: Flora
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020261:Arsenic Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018053:Arsenites; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017670:Sodium Compounds; D004113:Succimer / Q000031:analogs & derivatives* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018053:Arsenites; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D017670:Sodium Compounds; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; C017947:sodium arsenite; C091888:monoisoamyl-2,3-dimercaptosuccinate; D004113:Succimer; D053148:Caspase 3; D002118:Calcium