Arsenic and Oxidative Stress in Pentylenetetrazole-induced Seizures in Mice

Document Type : Research Paper


1 Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

3 Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Department of Pharmacology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

5 Nanotechnology Research Center, Department of Pharmaceutics, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.


Background and Objective: Chronic arsenic toxicity is a widespread problem; the role of brain oxidative stress has been suggested in the genesis of epilepsy and in the post-seizure neuronal death. However, studies investigating the effects of arsenic on seizure and related mechanisms are limited. The purpose of this study was to examine the effect of prolonged exposure to sodium arsenite on oxidative damage in pentylenetetrazole (PTZ)-induced seizures in mice.
Materials and Methods: In this study, male NMRI mice received sodium arsenite (0, 25, 50, and 100 ppm) in the drinking water for a period of 30 days. After exposure, all animals were injected PTZ (PTZ; 85 mg/kg, i.p.) to induce seizure, and the seizure parameters were evaluated for 30 minutes. Then, the levels of malondialdehyde (MDA) and reduced glutathione (GSH) were measured in the brain.  
Results: The results of this study showed that sodium arsenite decreases the latency to the seizure onset and time of death (p<0.05). The greatest effect was observed at concentration of 50 ppm. The data indicated that exposure to sodium arsenite increases the levels of MDA (p<0.05) and decreased the levels of GSH in brain (p<0.05).
Conclusion: Our results suggest that PTZ effects potentiated by arsenic and oxidative damage involved in exacerbation of arsenic convulsive effects. Considering the role of arsenic in brain tissue damage following the seizure, it is recommended to control arsenic in drinking water.


  1. Klaassen CD. Casarett & Doull's Toxicology: The Basic Science of Poisons: McGraw-Hill Education / Medical; 8 edition 2013.
  2. Ratnaike RN. Acute and chronic arsenic toxicity. Postgraduate Medical Journal 2003;79 (933): 391-6.
  3. Nordstrom DK. Worldwide occurrences of arsenic in ground water. American Association for the Advancement of Science 2002.
  4. Coronado-González JA, Del Razo LM, García-Vargas G, Sanmiguel-Salazar F, Escobedo-de la Peña J. Inorganic arsenic exposure and type 2 diabetes mellitus in Mexico. Environmental Research 2007;104(3):383-9.
  5. Sun G. Arsenic contamination and arsenicosis in China. Toxicology and Applied Pharmacology 2004;198(3):268-71.
  6. Hopenhayn-Rich C, Biggs ML, Smith AH. Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina. International Journal of Epidemiology 1998;27(4):561-9.
  7. Mosaferi M, Yunesian M, Dastgiri S, Mesdaghinia A, Esmailnasab N. Prevalence of skin lesions and exposure to arsenic in drinking water in Iran. Science of the Total Environment 2008;390(1):69-76.
  8. Chowdhury UK, Biswas BK, Chowdhury TR, Samanta G, Mandal BK, Basu GC, et al. Groundwater arsenic contamination in Bangladesh and West Bengal, India. Environmental Health Perspectives 2000;108(5):393.
  9. Pryor G, Uyeno E, Tilson H, Mitchell C. Assessment of chemicals using a battery of neurobehavioral tests: a comparative study. Neurobehavioral Toxicology and Teratology 1982;5(1):91-117.
  10. Rao M, Avani G. Arsenic induced free radical toxicity in brain of mice. Indian Journal of Experimental Biology 2004; 42(5):495-8·
  11. Piao F, Ma N, Hiraku Y, Murata M, Oikawa S, Cheng F, et al. Oxidative DNA damage in relation to neurotoxicity in the brain of mice exposed to arsenic at environmentally relevant levels. Journal of Occupational Health 2005;47(5):445-9.
  12. Ma N, Sasoh M, Kawanishi S, Sugiura H, Piao F. Protection effect of taurine on nitrosative stress in the mice brain with chronic exposure to arsenic. Journal of Biomedical Science 2010;17(1):S7.
  13. Flora SJ, Bhadauria S, Pant SC, Dhaked RK. Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats. Life Sciences 2005;77(18):2324-37.
  14. Vahidnia A, Van der Voet G, De Wolff F. Arsenic neurotoxicity—a review. Human & Experimental Toxicology 2007;26(10):823-32.
  15. Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clinica Chimica Acta 2001;303(1):19-24.
  16. Patel MN. Oxidative stress, mitochondrial dysfunction, and epilepsy. Free Radical Research 2002;36(11):1139-46.
  17. Liang L-P, Patel M. Mitochondrial oxidative stress and increased seizure susceptibility in Sod2−/+ mice. Free Radical Biology and Medicine 2004;36(5):542-54.
  18. Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, et al. Arsenic: toxicity, oxidative stress and human disease. Journal of Applied Toxicology 2011;31(2):95-107.
  19. Kitchin KT, Ahmad S. Oxidative stress as a possible mode of action for arsenic carcinogenesis. Toxicology Letters 2003;137(1-2):3-13.
  20. Mueller S, Trabesinger A, Boesiger P, Wieser H. Brain glutathione levels in patients with epilepsy measured by in vivo 1H-MRS. Neurology 2001;57(8):1422-7.
  21. Bashkatova V, Narkevich V, Vitskova G, Vanin A. The influence of anticonvulsant and antioxidant drugs on nitric oxide level and lipid peroxidation in the rat brain during penthylenetetrazole-induced epileptiform model seizures. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2003; 27(3):487-92.
  22. Patsoukis N, Zervoudakis G, Panagopoulos NT, Georgiou CD, Angelatou F, Matsokis NA. Thiol redox state (TRS) and oxidative stress in the mouse hippocampus after pentylenetetrazol-induced epileptic seizure. Neuroscience Letters 2004; 357(2):83-6.
  23. Uma Devi P, Kolappa Pillai K, Vohora D. Modulation of pentylenetetrazole‐induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N‐acetylcysteine. Fundamental & Clinical Pharmacology 2006;20(3):247-53.
  24. Yusuf M, Khan RA, Khan M, Ahmed B. Plausible antioxidant biomechanics and anticonvulsant pharmacological activity of brain-targeted β-carotene nanoparticles. International Journal of Nanomedicine 2012;7:4311.
  25. Rauca C, Wiswedel I, Zerbe R, Keilhoff G, Krug M. The role of superoxide dismutase and α-tocopherol in the development of seizures and kindling induced by pentylenetetrazol-influence of the radical scavenger α-phenyl-N-tert-butyl nitrone. Brain Research 2004;1009(1):203-12.
  26. Ekonomou A, Angelatou F. Upregulation of NMDA receptors in hippocampus and cortex in the pentylenetetrazol-induced “kindling” model of epilepsy. Neurochemical Research 1999;24(12):1515-22.
  27. Paul DS, Walton FS, Saunders RJ, Stýblo M. Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet. Environmental Health Perspectives 2011;119(8):1104.
  28. Vahidnia A, van der Straaten R, Romijn F, Van Pelt J, van der Voet G, de Wolff F. Arsenic metabolites affect expression of the neurofilament and tau genes: An in-vitro study into the mechanism of arsenic neurotoxicity. Toxicology in Vitro 2007;21(6):1104-12.
  29. Yen CC, Ho TJ, Wu CC, Chang CF, Su CC, Chen YW, et al. Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. Archives of Toxicology 2011;85(6):565-75.
  30. Gopalkrishnan A, Rao MV. Amelioration by vitamin A upon arsenic induced metabolic and neurotoxic effects. Journal of Health Science 2006;52(5):568-77.
  31. Kaneko K, Itoh K, Berliner LJ, Miyasaka K, Fujii H. Consequences of nitric oxide generation in epileptic‐seizure rodent models as studied by in vivo EPR. Magnetic Resonance in Medicine 2002;48(6):1051-6.
  32. Kudin AP, Kudina TA, Seyfried J, Vielhaber S, Beck H, Elger CE, et al. Seizure‐dependent modulation of mitochondrial oxidative phosphorylation in rat hippocampus. European Journal of Neuroscience 2002;15(7):1105-14.
  33. Ilhan A, Iraz M, Gurel A, Armutcu F, Akyol O. Caffeic acid phenethyl ester exerts a neuroprotective effect on CNS against pentylenetetrazol-induced seizures in mice. Neurochemical Research 2004;29(12):2287-92.
  34. Shi H, Shi X, Liu KJ. Oxidative mechanism of arsenic toxicity and carcinogenesis. Molecular and Cellular Biochemistry 2004;255(1-2):67-78.
  35. Pourahmad J, Rabiei M, Jokar F, O’Brien PJ. A comparison of hepatocyte cytotoxic mechanisms for chromate and arsenite. Toxicology 2005;206(3):449-60.
  36. Yamanaka K, Hoshino M, Okamoto M, Sawamura R, Hasegawa A, Okada S. Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical. Biochemical and Biophysical Research Communications 1990;168(1):58-64.
  37. Henkler F, Brinkmann J, Luch A. The role of oxidative stress in carcinogenesis induced by metals and xenobiotics. Cancers 2010;2(2):376-96.
  38. Yen CC, Ho TJ, Wu CC, Chang CF, Su CC, Chen YW, et al. Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. Archives of Toxicology 2011;85(6):565-75.
  39. BonakdarYazdi B, Khodagholi F, Shaerzadeh F, Sharifzadeh A, Ahmadi R, Sanati M, et al. The effect of arsenite on spatial learning: Involvement of autophagy and apoptosis. European Journal of Pharmacology 2017;796:54-61.
  40. Komissarova EV, Saha SK, Rossman TG. Dead or dying: the importance of time in cytotoxicity assays using arsenite as an example. Toxicology and Applied Pharmacology 2005;202(1):99-107.
  41. Rodrıguez V, Carrizales L, Jimenez-Capdeville M, Dufour L, Giordano M. The effects of sodium arsenite exposure on behavioral parameters in the rat. Brain Research Bulletin 2001;55(2):301-8.