Journal of Neurology

, Volume 254, Issue 12, pp 1676–1683 | Cite as

Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects

A cross-sectional study
  • N. Klepac
  • M. Relja
  • R. Klepac
  • S. Hećimović
  • T. Babić
  • V. Trkulja
ORIGINAL COMMUNICATION

Abstract

Background

Animal data and postmortem studies suggest a role of oxidative stress in the Huntington's disease (HD), but in vivo human studies have been scarce.

Aim

To assess the presence of oxidative stress in HD patients and its occurrence relative to clinical symptoms.

Methods

Oxidative stress markers were determined in plasma of HD patients (n = 19), asymptomatic HD gene carriers (with > 38 CAG repeats) (n = 11) and their respective sex and agematched healthy controls (n = 47 and n = 22) in a cross-sectional study.

Results

With adjustment for age and sex, HD patients had higher plasma lipid peroxidation (LP) levels (ratio 1.20, 95% CI 1.09 to 1.32, p < 0.001) and lower reduced glutathione (GSH) levels (ratio 0.72, CI 0.55 to 0.94, p = 0.011) than their age and sex-matched controls. Although considerably younger, HD gene carriers did not differ from HD patients regarding LP and GSH levels, and had higher plasma LP (ratio 1.16, CI 1.02 to 1.32, p = 0.016) and lower GSH than their matched controls (ratio 0.73, CI 0.5 to 1.05). They had higher LP (ratio 1.18, CI 1.02 to 1.34, p = 0.019) and lower GSH (ratio 0.75, CI 0.51 to 1.11) than the healthy subjects matched to HD patients.

Conclusions

Oxidative stress is more pronounced in HD patients and asymptomatic HD gene carriers than in healthy subjects. Differences in plasma LP and GSH are in line with the brain findings in animal models of HD. Data suggest that oxidative stress occurs before the onset of the HD symptoms.

Key words

Huntington's disease oxidative stress Unified Huntington's Disease Rating Scale (UHDRS) lipid peroxidation reduced glutathione 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Albers DS, Beal MF (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm 59:133–154Google Scholar
  2. 2.
    Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10:18–25CrossRefGoogle Scholar
  3. 3.
    Bates G (2003) Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361:1642–1644PubMedCrossRefGoogle Scholar
  4. 4.
    Beal MF (2000) Mechanisms of cell death in neurodegenerative disorders. Eur J Neurol 7 (Suppl. 2):1–4Google Scholar
  5. 5.
    Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington's disease. Brain Pathol 9:147–163PubMedCrossRefGoogle Scholar
  6. 6.
    Brouillet E, Jacquard C, Bizat N, Blum D (2005) 3-Nitropropionic acid: a mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in Huntington's disease. J Neurochem 95:1521–1540PubMedCrossRefGoogle Scholar
  7. 7.
    Butterfield DA,Kanski J (2001) Brain protein oxidation in age-related neurodegenerative disorder that are associated with aggregated proteins. Mech Ageing Dev 122:945–962PubMedCrossRefGoogle Scholar
  8. 8.
    Christofiades J, Bridel M, Egerton M, Mackay GM, Forrest CM, Stoy N, Darlington LG, Stone TW (2006) Blood 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and melatonin levels in patients with either Huntington's disease or chronic brain injury. J Neurochem 97:1078–1088CrossRefGoogle Scholar
  9. 9.
    Delanty N, Dichter MA (2000) Antioxidant therapy in neurological diseases. Arch Neurol 57:1265–1270PubMedCrossRefGoogle Scholar
  10. 10.
    Dringen R,Hirrlinger J (2003) Glutathione pathways in the brain. Biol Chem 384:505–516PubMedCrossRefGoogle Scholar
  11. 11.
    Feigin A, Zgaljardic D (2002) Recent advances in Huntington's disease: implications for experimental therapeutics. Curr Opin Neurol 15:483–489PubMedCrossRefGoogle Scholar
  12. 12.
    Hague SM,Klaffke S, Bandmann O (2005) Neurodegenerative disorders: Parkinson's disease and Huntington's disease. J Neurol Neurosurg Psychiatry 76:1058–1063PubMedCrossRefGoogle Scholar
  13. 13.
    Hećimović S, Klepac N, Vlašić J,Vojta A, Janko D, Škarpa-Prpić I, Canki- Klain N,Marković D, Božikov J, Relja M, Pavelić K (2002) Genetic background of Huntington disease in Croatia:Molecular analysis of CAG, CCG, and Delta2642 (E2642del) polymorphisms. Hum Mutat 20:233PubMedCrossRefGoogle Scholar
  14. 14.
    del Hoyo P, Garcia-Redondo A, de Bustos F,Molina JA, Sayed Y, Alonso-Navarro H, Caballero L, Arenas J, Jimenez-Jimenez FJ (2006) Oxidative stress in skin fibroblasts cultures of patients with Huntington's disease. Neurochem Res 31:1103–1109PubMedCrossRefGoogle Scholar
  15. 15.
    Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosome. Cell 72: 971–983CrossRefGoogle Scholar
  16. 16.
    Huntington Study Group (1996) Unified Huntington's disease rating scale: reliability and consistency. Mov Disord 11:136–142CrossRefGoogle Scholar
  17. 17.
    Inoue M, Koyama K (1994) Determination of superoxide and vitamine C radicals using cytochrome c and superoxide dismutase derivatives. Methods Enzymol 56:338–343Google Scholar
  18. 18.
    Johansson LH, Borg LA (1988) A spectrophotometric method for determination of catalase activity in small tissue samples. Anal Biochem 174:331–336PubMedCrossRefGoogle Scholar
  19. 19.
    Lang C,Naryshin S, Schneider DL, Mills BJ, Linderman RD (1992) Low blood glutathione levels in healthy aging adult. J Lab Clin Med 20:720–725Google Scholar
  20. 20.
    Levine RL, Gardland D, Olivier CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478PubMedCrossRefGoogle Scholar
  21. 21.
    Lowry OH, Rosebrough NJ, Farr AL, Randall LJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:263–275Google Scholar
  22. 22.
    Mariani E, Polidori MC, Cherubini A, Mecocci P (2005) Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B Analyt Technol Biomed Life Sci 827:65–75PubMedCrossRefGoogle Scholar
  23. 23.
    Marklund S,Marklund G (1974) Involvement of the superoxide anion radical in the antioxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474PubMedCrossRefGoogle Scholar
  24. 24.
    Myers RH (2004) Huntington's disease genetics. NeuroRx 1:255–262PubMedCrossRefGoogle Scholar
  25. 25.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxidases in animal tissue by thiobarbituric acid reaction. Annal Biochem 95:351–358CrossRefGoogle Scholar
  26. 26.
    Perez-Severiano F, Rios C, Segovia J (2000) Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington's disease. Brain Res 862:234–237PubMedCrossRefGoogle Scholar
  27. 27.
    Santamaria A, Perez-Severiano F, Rodriquez-Martinez E, Maldonado PD, Pedraza-Chaverri J, Rios C, Segovia J (2001) Comparative analysis of superoxide dismutase activity between acute pharmacological models and transgenic mouse model of Huntington's disease. Neurchem Res 26:419–424CrossRefGoogle Scholar
  28. 28.
    Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P,Marsden CD (1994) Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36:348–355PubMedCrossRefGoogle Scholar
  29. 29.
    Stoy N, Mackay GM, Forrest CM, Christofides J, Egerton M, Stone TW, Darlington LG (2005) Tryptophan metabolism and oxidative stress in patients with Huntington's disease. J Neurochem 93:611–623PubMedCrossRefGoogle Scholar
  30. 30.
    Taiq M, Khan HA, Elfaki I, Al Deeb S, Al Moutaery K (2005) Neuroprotective effect of nicotine against 3-nitropropionic acid (3-NP)-induced experimental Huntington's disease in rats. Brain Res Bull 67:161–168CrossRefGoogle Scholar
  31. 31.
    Tarpey MM; Fridovich I (2001) Methods of detection of vascular reactive species: nitric oxide, superoxide, hydrogen peroxide and peroxynitrite. Circ Res 89:224–236PubMedCrossRefGoogle Scholar
  32. 32.
    Warner JP, Barron LH, Brock DJH (1993) A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. Molecular Cellular Probes 7:235–239CrossRefGoogle Scholar
  33. 33.
    Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–247PubMedCrossRefGoogle Scholar

Copyright information

© Steinkopff Verlag 2007

Authors and Affiliations

  • N. Klepac
    • 1
  • M. Relja
    • 1
  • R. Klepac
    • 2
  • S. Hećimović
    • 3
  • T. Babić
    • 1
  • V. Trkulja
    • 4
  1. 1.Dept. of NeurologyUniversity Clinical Hospital Center Zagreb, Zagreb University School of MedicineZagrebCroatia
  2. 2.Dept. of Biology ZagrebUniversity School of MedicineZagrebCroatia
  3. 3.Division of Molecular MedicineRuđer Bošković InstituteZagrebCroatia
  4. 4.Dept. of PharmacologyZagreb University School of MedicineZagrebCroatia

Personalised recommendations