Applied Biochemistry and Biotechnology

, Volume 186, Issue 1, pp 27–39 | Cite as

Protective Effect of Hydroxytyrosol Against Oxidative Stress Mediated by Arsenic-Induced Neurotoxicity in Rats

  • Manisha Soni
  • Chandra Prakash
  • Rajesh Dabur
  • Vijay KumarEmail author


The present study reports beneficial effect of hydroxytyrosol (HT) against arsenic (As)-induced oxidative stress in the rat brain. Rats were orally administered with sodium arsenite dissolved in distilled water (25 ppm, by oral gavage) for 8 weeks or HT (10 mg/kg b. wt.) in combination with As. Results showed increase in protein oxidation and lipid peroxidation, while catalase and superoxide dismutase (SOD) activities as well as GSH content were decreased after As exposure in rat brain. Fourier transform infrared analysis showed significant alteration in peak area values that also validated the oxidative damage to lipids and proteins. In addition, As exposure caused increase in protein expression of caspase-3 and Bax, while Bcl-2 expression was downregulated resulting in translocation of cytochrome c from mitochondria to cytosol. Treatment of HT with As reversed protein oxidation, lipid peroxidation, and increased GSH content as well as catalase and SOD activities. Administration of HT also prevented translocation of cytochrome c from mitochondria and increased mitochondria/cytosol ratio of cytochrome c. Hence, treatment of HT with As improved antioxidant system and efficiently lowered the generation of oxidative stress in rat brain.


Arsenic Hydroxytyrosol Oxidative stress FTIR Neurotoxicity 



The financial assistance for the present work was provided by Indian Council of Medical Research, New Delhi, India (grant No 58/51/2011-BMS), in the form of ad hoc scheme project sanctioned to Vijay Kumar. Authors also acknowledge Department of Science and Technology, New Delhi, for providing research infrastructural facilities in the form of FIST program (grant no. SR/FST/LSI-534/2012).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Chowdhury, U. K., Biswas, B. K., Chowdhury, T. R., Samanta, G., Mandal, B. K., Basu, G. C., Chanda, C. R., Lodh, D., Saha, K. C., Mukherjee, S. K., & Roy, S. (2000). Groundwater arsenic contamination in Bangladesh and West Bengal, India. Environmental Health Perspectives, 108(5), 393–397.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Singh, A. P., Goel, R. K., & Kaur, T. (2011). Mechanisms pertaining to arsenic toxicity. Toxicology International, 18(2), 87–93.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rodriguez-Barranco, M., Lacasana, M., Aguilar-Garduno, C., Alguacil, J., Gil, F., Gonzalez-Alzaga, B., & Rojas-Garcia, A. (2013). Association of arsenic, cadmium and manganese exposure with neurodevelopment and behavioural disorders in children: a systematic review and meta-analysis. Sci Total Environ, 454-455, 562–577.CrossRefPubMedGoogle Scholar
  4. 4.
    Yen, C. C., Ho, T. J., Wu, C. C., Chang, C. F., Su, C. C., Chen, Y. W., Jinn, T. R., Lu, T. H., Cheng, P. W., Su, Y. C., & Liu, S. H. (2011). Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway. Archives of Toxicology, 85(6), 565–575.CrossRefPubMedGoogle Scholar
  5. 5.
    Rodriguez, V. M., Carrizales, L., Mendoza, M. S., Fajardo, O. R., & Giordano, M. (2002). Effects of sodium arsenite exposure on development and behavior in the rat. Neurotoxicology and Teratology, 24(6), 743–570.CrossRefPubMedGoogle Scholar
  6. 6.
    Shulman, R. G., Rothman, D. L., Behar, K. L., & Hyder, F. (2004). Energetic basis of brain activity: implications for neuroimaging. Trends in Neurosciences, 27(8), 489–495.CrossRefPubMedGoogle Scholar
  7. 7.
    Birben, E., Sahiner, U. M., Sackesen, C., Erzurum, S., & Kalayci, O. (2012). Oxidative stress and antioxidant defense. World Allergy Organization Journal, 5(1), 9–19.CrossRefPubMedGoogle Scholar
  8. 8.
    Prakash, C., Soni, M., & Kumar, V. (2015). Biochemical and molecular alterations following arsenic-induced oxidative stress and mitochondrial dysfunction in rat brain. Biological Trace Element Research, 167(1), 121–129.CrossRefPubMedGoogle Scholar
  9. 9.
    Rios, R., Zarazua, S., Santoyo, M. E., Sepulveda-Saavedra, J., Romero-Diaz, V., Jimenez, V., Perez-Severiano, F., Vidal-Cantu, G., Delgado, J. M., & Jimenez-Capdeville, M. E. (2009). Decreased nitric oxide markers and morphological changes in the brain of arsenic-exposed rats. Toxicology, 261(1–2), 68–75.CrossRefPubMedGoogle Scholar
  10. 10.
    Bashir, S., Sharma, Y., Irshad, M., Gupta, S. D., & Dogra, T. D. (2006). Arsenic-induced cell death in liver and brain of experimental rats. Basic & Clinical Pharmacology & Toxicology, 98(1), 38–43.CrossRefGoogle Scholar
  11. 11.
    Yadav, R. S., Sankhwar, M. L., Shukla, R. K., Chandra, R., Pant, A. B., Islam, F., & Khanna, V. K. (2009). Attenuation of arsenic neurotoxicity by curcumin in rats. Toxicology and Applied Pharmacology, 240(3), 367–376.CrossRefPubMedGoogle Scholar
  12. 12.
    Flora, S. J. S., Bhadauria, S., Pant, S. C., & Dhaked, R. K. (2005). Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats. Life Sciences, 77(18), 2324–2337.CrossRefPubMedGoogle Scholar
  13. 13.
    Goya, L., Mateos, R., & Bravo, L. (2007). Effect of the olive oil phenol hydroxytyrosol on human hepatoma HepG2 cells. Protection against oxidative stress induced by tert-butylhydroperoxide. European Journal of Nutrition, 46(2), 70–78.CrossRefPubMedGoogle Scholar
  14. 14.
    De la Puerta, R., Ruiz Gutierrez, V., & Hoult, J. R. (1999). Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochemical Pharmacology, 57(4), 445–449.CrossRefPubMedGoogle Scholar
  15. 15.
    Manna, C., Galletti, P., Cucciolla, V., Montedoro, G., & Zappia, V. (1999). Olive oil hydroxytyrosol protects human erythrocytes against oxidative damages. The Journal of Nutritional Biochemistry, 10(3), 159–165.CrossRefPubMedGoogle Scholar
  16. 16.
    Zou, X., Feng, Z., Li, Y., Wang, Y., Wertz, K., Weber, P., Fu, Y., & Liu, J. (2012). Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways. The Journal of Nutritional Biochemistry, 23(8), 994–1006.CrossRefPubMedGoogle Scholar
  17. 17.
    Pan, S., Liu, L., Pan, H., Ma, Y., Wang, D., Kang, K., Wang, J., Sun, B., Sun, X., & Jiang, H. (2013). Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. Molecular Nutrition & Food Research, 57(7), 1218–1227.CrossRefGoogle Scholar
  18. 18.
    Kitsati, N., Mantzaris, M. D., & Galaris, D. (2016). Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation. Redox Biology, 10, 233–242.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jemai, H., El Feki, A., & Sayadi, S. (2009). Antidiabetic and antioxidant effects of hydroxytyrosol and oleuropein from olive leaves in alloxan-diabetic rats. Journal of Agricultural and Food Chemistry, 57(19), 8798–8804.CrossRefPubMedGoogle Scholar
  20. 20.
    Zheng, A., Li, H., Xu, J., Cao, K., Li, H., Pu, W., Yang, Z., Peng, Y., Long, J., Liu, J., & Feng, Z. (2015). Hydroxytyrosol improves mitochondrial function and reduces oxidative stress in the brain of db/db mice: role of AMP-activated protein kinase activation. The British Journal of Nutrition, 113(11), 1667–1676.CrossRefPubMedGoogle Scholar
  21. 21.
    Ristagno, G., Fumagalli, F., Porretta-Serapiglia, C., Orru, A., Cassina, C., Pesaresi, M., Masson, S., Villanova, L., Merendino, A., Villanova, A., & Cervo, L. (2012). Hydroxytyrosol attenuates peripheral neuropathy in streptozotocin-induced diabetes in rats. Journal of Agricultural and Food Chemistry, 60(23), 5859–5865.CrossRefPubMedGoogle Scholar
  22. 22.
    De La Cruz, J. P., Ruiz-Moreno, M. I., Guerrero, A., Reyes, J. J., Benitez-Guerrero, A., Espartero, J. L., & Gonzalez-Correa, J. A. (2015). Differences in the neuroprotective effect of orally administered virgin olive oil (Olea europaea) polyphenols tyrosol and hydroxytyrosol in rats. Journal of Agricultural and Food Chemistry, 63(25), 5957–5963.CrossRefGoogle Scholar
  23. 23.
    Wills, E. D. (1966). Mechanisms of lipid peroxide formation in animal tissues. The Biochemical Journal, 99(3), 667–676.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Levine, R. L., Williams, J. A., Stadtman, E. R., & Shacter, E. (1994). Carbonyl assays for determination of oxidatively modified proteins. Methods in Enzymology, 233, 346–357.CrossRefPubMedGoogle Scholar
  25. 25.
    Kono, Y. (1978). Generation of superoxide radical during autooxidation of hydroxylamine and an assay for superoxide dismutase. Archives of Biochemistry and Biophysics, 186(1), 189–195.CrossRefPubMedGoogle Scholar
  26. 26.
    Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1), 70–77.CrossRefPubMedGoogle Scholar
  27. 27.
    Akkas, S. B., Severcan, M., Yilmaz, O., & Severcan, F. (2007). Effects of lipoic acid supplementation on rat brain tissue: an FTIR spectroscopic and neural network study. Food Chemistry, 105(3), 1281–1288.CrossRefGoogle Scholar
  28. 28.
    Lowry, O. H., Rosenbrough, N. J., Farr, A., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry, 193(1), 265–275.PubMedGoogle Scholar
  29. 29.
    da Rocha, P. D. S., Campos, J. F., Nunes-Souza, V., do Carmo Vieira, M., de Araujo Boleti, A. P., Rabelo, L. A., dos Santos, E. L., & de Picoli Souza, K. (2017). Antioxidant and protective effects of Schinus terebinthifolius raddi against doxorubicin-induced toxicity. Applied Biochemistry and Biotechnology, 1–16.Google Scholar
  30. 30.
    Ramakrishnan, R., Elangovan, P., & Pari, L. (2017). Protective role of Tetrahydrocurcumin: an active polyphenolic curcuminoid on cadmium-InducedOxidative damage in rats. Applied Biochemistry and Biotechnology, 183(1), 51–69.CrossRefPubMedGoogle Scholar
  31. 31.
    Muthuraman, P., Ramkumar, K., & Kim, D. H. (2014). Analysis of dose-dependent effect of zinc oxide nanoparticles on the oxidative stress and antioxidant enzyme activity in adipocytes. Applied Biochemistry and Biotechnology, 174(8), 2851–2874.CrossRefPubMedGoogle Scholar
  32. 32.
    Chen, Y. W., Huang, C. F., Yang, C. Y., Yen, C. C., Tsai, K. S., & Liu, S. H. (2010). Inorganic mercury causes pancreatic β-cell death via the oxidative stress-induced apoptotic and necrotic pathways. Toxicology and Applied Pharmacology, 243(3), 323–331.CrossRefPubMedGoogle Scholar
  33. 33.
    Gutteridge, J., & Quinlan, G. J. (1983). Malondialdehyde formation from lipid peroxides in the thiobarbituric acid test: the role of lipid radicals, iron salts, and metal chelators. Journal of Applied Biochemistry, 5(4–5), 293–299.PubMedGoogle Scholar
  34. 34.
    Ghosh, A., Mandal, A. K., Sarkar, S., & Das, N. (2011). Hepatoprotective and neuroprotective activity of liposomal quercetin in combating chronic arsenic induced oxidative damage in liver and brain of rats. Drug Delivery, 18(6), 451–459.CrossRefPubMedGoogle Scholar
  35. 35.
    Kumar, M. R., Flora, S. J. S., & Reddy, G. R. (2013). Monoisoamyl 2, 3-dimercaptosuccinic acid attenuates arsenic induced toxicity: behavioral and neurochemical approach. Environmental Toxicology and Pharmacology, 36(1), 231–242.CrossRefGoogle Scholar
  36. 36.
    Nehru, L. B., & Bansal, M. P. (1996). Effect of selenium supplementation on the glutathione redox system in the kidney of mice after chronic cadmium exposures. Journal of Applied Toxicology, 17(1), 81–84.CrossRefGoogle Scholar
  37. 37.
    Shila, S., Kokilavani, V., Subathra, M., & Panneerselvam, C. (2005). Brain regional responses in antioxidant system to α-lipoic acid in arsenic intoxicated rat. Toxicology, 210(1), 25–36.CrossRefPubMedGoogle Scholar
  38. 38.
    Ramos, O., Carrizales, L., Yanez, L., Mejia, J., Batres, L., Ortiz, D., & Diaz-Barriga, F. (1995). Arsenic increased lipid peroxidation in rat tissues by a mechanism independent of glutathione levels. Environmental Health Perspectives, 103(1), 85–88.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Schieber, M., & Chandel, N. S. (2014). ROS function in redox signaling and oxidative stress. Current Biology, 24(10), R453–R462.CrossRefPubMedGoogle Scholar
  40. 40.
    Moraes, T. B., Jacques, C. E. D., Rosa, A. P., Dalazen, G. R., Terra, M., Coelho, J. G., & Dutra-Filho, C. S. (2013). Role of catalase and superoxide dismutase activities on oxidative stress in the brain of a phenylketonuria animal model and the effect of lipoic acid. Cellular and Molecular Neurobiology, 33(2), 253–260.CrossRefPubMedGoogle Scholar
  41. 41.
    Jomova, K., Jenisova, Z., Feszterova, M., Baros, S., Liska, J., Hudecova, D., Rhodes, C. J., & Valko, M. (2011). Arsenic: toxicity, oxidative stress and human disease. Journal of Applied Toxicology, 31(2), 95–107.PubMedGoogle Scholar
  42. 42.
    Dispersyn, G., Nuydens, R., Connors, R., Borgers, M., & Geerts, H. (1999). Bcl-2 protects against FCCP-induced apoptosis and mitochondrial membrane potential depolarization in PC12 cells. Biochimica et Biophysica Acta, 1428(2–3), 357–371.CrossRefPubMedGoogle Scholar
  43. 43.
    Arunsundar, M., Shanmugarajan, T. S., & Ravichandran, V. (2015). 3,4-Dihydroxyphenylethanol attenuates spatio-cognitive deficits in an Alzheimer’s disease mouse model: modulation of the molecular signals in neuronal survival-apoptotic programs. Neurotoxicity Research, 27(2), 143–155.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiochemistryMaharshi Dayanand UniversityRohtakIndia

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