Skip to main content
Log in

Neuroprotective effects of chronic hesperetin administration in mice

  • Research Article
  • Drug Efficacy and Safety
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Flavonoids are considered therapeutic agents in neurodegenerative disease because of their neuroprotective activity. This study investigated the neuroprotective effects of hesperetin in the brains of mice administered hesperetin at 10 or 50 mg/kg body weight (BW) for five weeks. Hesperetin inhibited biomarkers of oxidative stress, such as the level of thiobarbituric acid-reactive substance (TBARS) and carbonyl content, although there was a significant reduction at the higher dose of hesperetin. Moreover, at the higher dose, hesperetin significantly activated the catalase and total superoxide dismutase (SOD) activities. The same patterns were observed in the protein expression, and the expression of CuZn-SOD was more pronounced than that of Mn-SOD. The reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio was increased significantly in a dose-dependent manner, as well as the glutathione peroxidase (GSH-px) and glutathione reductase (GR) activities. Moreover, hesperetin did not induce apoptosis, even at the higher dose, as evidenced by caspase-3 expression and its activity. Based on these results, hesperetin may have a neuroprotective effect via the inhibition of oxidative damage, together with activation of the antioxidant enzyme system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adams, J. D. Jr., Klaidman, L. K., Odunze, I. N., Shen, H. C., and Miller, C. A., Alzheimer’s and Parkinson’s disease. Brain levels of glutathione, glutathione disulfide, and vitamin E. Mol. Chem. Neuropathol., 14, 213–226 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Aebi, H., Catalase in vitro. Methods Enzymol., 105, 121–126 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Aldini, G., Dalle-Donne, I., Facino, R. M., Milzani, A., and Carini, M., Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls. Med. Res. Rev., 27, 817–868 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Ansari, M. A., Joshi, G., Huang, Q., Opii, W. O., Abdul, H. M., Sultana, R., and Butterfield, D. A., In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders. Free Radic. Biol. Med., 41, 1694–1703 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Bharath, S., Hsu, M., Kaur, D., Rajagopalan, S., and Andersen, J. K., Glutathione, iron and Parkinson’s disease. Biochem. Pharmacol., 64, 1037–1048 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Bonilla, E., Huntington disease. Invest. Clin., 41, 117–141 (2000).

    PubMed  CAS  Google Scholar 

  • Carlberg, I. and Mannervik, B., Glutathione reductase. Methods Enzymol., 113, 484–490 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Cho, J., Antioxidant and neuroprotective effects of hesperidin and its aglycone hesperetin. Arch. Pharm. Res., 29, 699–706 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Choi, E. J., Kim, G. D., Chee, K. M., and Kim, G. H., Effects of hesperetin on vessel structure formation in mouse embryonic stem (mES) cells. Nutrition, 22, 947–951 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Choi, E. J., Antioxidative effects of hesperetin against 7,12-dimethylbenz(a)anthracene-induced oxidative stress in mice. Life Sci., 82, 1059–1064 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Cooper, A. J. L., Glutathione in the brain: disorders of glutathione metabolism: The Molecular and Genetic Basis of Neurological Disease. Butterworth-Heinemann, Boston, 1997, pp. 1195–1230, (1997).

    Google Scholar 

  • Cruz-Aguado, R., Turner, L. F., Diaz, C. M., and Pinero, J., Nerve growth factor and striatal glutathione metabolism in a rat model of Huntington’s disease. Restor. Neurol. Neurosci., 17, 217–221 (2000).

    PubMed  CAS  Google Scholar 

  • Erdem, E., Carlier, R., Idir, A. B., Masnou, P. O., Moulonguet, A., Adams, D., and Doyon, D., Gadolinium-enhanced MRI in central nervous system Behçet’s disease. Neuroradiology, 35, 142–144 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Flohé, L. and Günzler, W. A., Assays of glutathione peroxidase. Methods Enzymol., 105, 114–121 (1984).

    Article  PubMed  Google Scholar 

  • Fridovich, I., Superoxide anion radical (O2−.), superoxide dismutases, and related matters. J. Biol. Chem., 272, 18515–18517 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Fridovich, I., Superoxide radical and superoxide dismutases. Annu. Rev. Biochem., 64, 97–112 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Garg, A., Garg, S., Zaneveld, L. J., and Singla, A. K., Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother. Res., 15, 655–669 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Hirrlinger, J., Schulz, J. B., and Dringen, R., Effects of dopamine on the glutathione metabolism of cultured astroglial cells: implications for Parkinson’s disease. J. Neurochem., 82, 458–467 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Hissin, P. J. and Hilf, R., A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal. Biochem., 74, 214–226 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Ho, Y. S., Magnenat, J. L., Bronson, R. T., Cao, J., Gargano, M., Sugawara, M., and Funk, C. D., Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J. Biol. Chem., 272, 16644–16651 (1997a).

    Article  PubMed  CAS  Google Scholar 

  • Ho, Y. S., Swenson, L., Derewenda, U., Serre, L., Wei, Y., Dauter, Z., Hattori, M., Adachi, T., Aoki, J., Arai, H., Inoue, K., and Derewenda, Z. S., Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. Nature, 385, 89–93 (1997b).

    Article  PubMed  CAS  Google Scholar 

  • Hwang, S. L. and Yen, G. C., Neuroprotective effects of the citrus flavanones against H2O2-induced cytotoxicity in PC12 cells. J. Agric. Food Chem., 859–864 (2008).

  • Jaeger, A., Wälti, M., and Neftel, K., Side effects of flavonoids in medical practice. Prog. Clin. Biol. Res., 280, 379–394 (1988).

    PubMed  CAS  Google Scholar 

  • Kim, J. Y., Jung, K. J., Choi, J. S., and Chung, H. Y., Hesperetin: a potent antioxidant against peroxynitrite. Free Radic. Res., 38, 761–769 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Marklund, S. and Marklund, G., Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur. J. Biochem., 47, 469–474 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Moreira, P. I., Siedlak, S. L., Aliev, G., Zhu, X., Cash, A. D., Smith, M. A., and Perry, G., Oxidative stress mechanisms and potential therapeutics in Alzheimer disease. J. Neural Transm., 112, 921–932 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Nunomura, A., Moreira, P. I., Lee, H. G., Zhu, X., Castellani, R. J., Smith, M. A., and Perry, G., Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. CNS Neurol. Disord. Drug Targets, 6, 411–423 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Ohkawa, H., Ohishi, N., and Yagi, K., Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem., 95, 351–358 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Pollard, S. E., Whiteman, M., and Spencer, J. P., Modulation of peroxynitrite-induced fibroblast injury by hesperetin: a role for intracellular scavenging and modulation of ERK signaling. Biochem. Biophys. Res. Commun., 347, 916–923 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Rao, A. V. and Balachandran, B., Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr. Neurosci., 5, 291–309 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Reznick, A. Z. and Packer, L., Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol., 233, 357–363 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Ross, J. A. and Kasum, C. M., Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr., 22, 19–34 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Sian, J., Dexter, D. T., Lees, A. J., Daniel, S., Agid, Y., Javoy-Agid, F., Jenner, P., and Marsden, C. D., Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol., 36, 348–355 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Suk, K., Regulation of neuroinflammation by herbal medicine and its implications for neurodegenerative diseases. A focus on traditional medicines and flavonoids. Neurosignals., 14, 23–33 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Zhu, Y., Carvey, P. M., and Ling, Z., Age-related changes in glutathione and glutathione-related enzymes in rat brain. Brain Res., 1090, 35–44 (2006).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Woong Shick Ahn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, E.J., Ahn, W.S. Neuroprotective effects of chronic hesperetin administration in mice. Arch. Pharm. Res. 31, 1457–1462 (2008). https://doi.org/10.1007/s12272-001-2130-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-001-2130-1

Key words

Navigation