Neurochemical Research

, Volume 38, Issue 3, pp 660–668

Probucol Affords Neuroprotection in a 6-OHDA Mouse Model of Parkinson’s Disease

  • Renata Pietsch Ribeiro
  • Eduardo Luiz Gasnhar Moreira
  • Danúbia Bonfanti Santos
  • Dirleise Colle
  • Alessandra Antunes dos Santos
  • Kaite Cristiane Peres
  • Claudia Pinto Figueiredo
  • Marcelo Farina
Original Paper

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic nigrostriatal neurons. Although the etiology of the majority of human PD cases is unknown, experimental evidence points to oxidative stress as an early and causal event. Probucol is a lipid-lowering phenolic compound with anti-inflammatory and antioxidant properties that has been recently reported as protective in neurotoxicity and neurodegeneration models. This study was designed to investigate the effects of probucol on the vulnerability of striatal dopaminergic neurons to oxidative stress in a PD in vivo model. Swiss mice were treated with probucol during 21 days (11.8 mg/kg; oral route). Two weeks after the beginning of treatment, mice received a single intracerebroventricular (i.c.v.) infusion of 6-hydroxydopamine (6-OHDA). On the 21st day, locomotor performance, striatal oxidative stress-related parameters, and striatal tyrosine hydroxylase and synaptophysin levels, were measured as outcomes of toxicity. 6-OHDA-infused mice showed hyperlocomotion and a significant decrease in striatal tyrosine hydroxylase (TH) and synaptophysin levels. In addition, 6-OHDA-infused mice showed reduced superoxide dismutase activity and increased lipid peroxidation and catalase activity in the striatum. Notably, probucol protected against 6-OHDA-induced hyperlocomotion and striatal lipid peroxidation, catalase upregulation and decrease of TH levels. Overall, the present results show that probucol protects against 6-OHDA-induced toxicity in mice. These findings may render probucol as a promising molecule for further pharmacological studies on the search for disease-modifying treatment in PD.

Keywords

Probucol Oxidative stress Parkinson’s disease 6-Hydroxydopamine Therapeutic strategies 

References

  1. 1.
    Lang AE, Lozano AM (1998) Parkinson’s disease. First of two parts. N Engl J Med 339(15):1044–1053. doi:10.1056/NEJM199810083391506 PubMedCrossRefGoogle Scholar
  2. 2.
    Meissner WG (2012) When does Parkinson’s disease begin? From prodromal disease to motor signs. Rev Neurol (Paris). doi:10.1016/j.neurol.2012.07.004 Google Scholar
  3. 3.
    Spica V, Pekmezovic T, Svetel M, Kostic VS (2012) Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson’s disease. J Neurol. doi:10.1007/s00415-012-6600-9 PubMedGoogle Scholar
  4. 4.
    Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 334(6180):345–348. doi:10.1038/334345a0 PubMedCrossRefGoogle Scholar
  5. 5.
    Schapira AH (2008) Progress in Parkinson’s disease. Eur J Neurol 15(1):1. doi:10.1111/j.1468-1331.2007.02036.x PubMedCrossRefGoogle Scholar
  6. 6.
    Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G (2010) Missing pieces in the Parkinson’s disease puzzle. Nat Med 16(6):653–661. doi:10.1038/nm.2165 PubMedCrossRefGoogle Scholar
  7. 7.
    Steece-Collier K, Maries E, Kordower JH (2002) Etiology of Parkinson’s disease: genetics and environment revisited. Proc Natl Acad Sci USA 99(22):13972–13974. doi:10.1073/pnas.242594999 PubMedCrossRefGoogle Scholar
  8. 8.
    Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36. doi:10.1002/ana.10483 (discussion S36–S28)PubMedCrossRefGoogle Scholar
  9. 9.
    Zhou C, Huang Y, Przedborski S (2008) Oxidative stress in Parkinson’s disease: a mechanism of pathogenic and therapeutic significance. Ann NY Acad Sci 1147:93–104. doi:10.1196/annals.1427.023 PubMedCrossRefGoogle Scholar
  10. 10.
    Lotharius J, Brundin P (2002) Pathogenesis of Parkinson’s disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 3(12):932–942. doi:10.1038/nrn983 PubMedCrossRefGoogle Scholar
  11. 11.
    Graham DG, Tiffany SM, Bell WR Jr, Gutknecht WF (1978) Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro. Mol Pharmacol 14(4):644–653PubMedGoogle Scholar
  12. 12.
    Fukae J, Mizuno Y, Hattori N (2007) Mitochondrial dysfunction in Parkinson’s disease. Mitochondrion 7(1–2):58–62. doi:10.1016/j.mito.2006.12.002 PubMedCrossRefGoogle Scholar
  13. 13.
    Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4(11):600–609. doi:10.1038/ncpneuro0924 PubMedCrossRefGoogle Scholar
  14. 14.
    Langston JW (1996) The etiology of Parkinson’s disease with emphasis on the MPTP story. Neurology 47(6 Suppl 3):S153–S160PubMedCrossRefGoogle Scholar
  15. 15.
    Chinta SJ, Andersen JK (2008) Redox imbalance in Parkinson’s disease. Biochim Biophys Acta 1780(11):1362–1367. doi:10.1016/j.bbagen.2008.02.005 PubMedCrossRefGoogle Scholar
  16. 16.
    Martin HL, Teismann P (2009) Glutathione–a review on its role and significance in Parkinson’s disease. FASEB J 23(10):3263–3272. doi:10.1096/fj.08-125443 PubMedCrossRefGoogle Scholar
  17. 17.
    Bove J, Perier C (2011) Neurotoxin-based models of Parkinson’s disease. Neuroscience 211:51–76. doi:10.1016/j.neuroscience.2011.10.057 PubMedCrossRefGoogle Scholar
  18. 18.
    Glinka Y, Gassen M, Youdim MB (1997) Mechanism of 6-hydroxydopamine neurotoxicity. J Neural Transm Suppl 50:55–66PubMedCrossRefGoogle Scholar
  19. 19.
    Kumar R, Agarwal AK, Seth PK (1995) Free radical-generated neurotoxicity of 6-hydroxydopamine. J Neurochem 64(4):1703–1707PubMedCrossRefGoogle Scholar
  20. 20.
    Saner A, Thoenen H (1971) Model experiments on the molecular mechanism of action of 6-hydroxydopamine. Mol Pharmacol 7(2):147–154PubMedGoogle Scholar
  21. 21.
    Group TPS (1993) Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 328(3):176–183. doi:10.1056/NEJM199301213280305 CrossRefGoogle Scholar
  22. 22.
    Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M (2002) Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 59(10):1541–1550PubMedCrossRefGoogle Scholar
  23. 23.
    Yamashita S, Hbujo H, Arai H, Harada-Shiba M, Matsui S, Fukushima M, Saito Y, Kita T, Matsuzawa Y (2008) Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb 15(6):292–303PubMedCrossRefGoogle Scholar
  24. 24.
    Champagne D, Pearson D, Dea D, Rochford J, Poirier J (2003) The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer’s disease. Neuroscience 121(1):99–110PubMedCrossRefGoogle Scholar
  25. 25.
    Park SY, Lee JH, Kim CD, Rhim BY, Hong KW, Lee WS (2007) Beneficial synergistic effects of concurrent treatment with cilostazol and probucol against focal cerebral ischemic injury in rats. Brain Res 1157:112–120. doi:10.1016/j.brainres.2007.04.051 PubMedCrossRefGoogle Scholar
  26. 26.
    Santos DB, Peres KC, Ribeiro RP, Colle D, dos Santos AA, Moreira EL, Souza DO, Figueiredo CP, Farina M (2012) Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid beta peptide in mice. Exp Neurol 233(2):767–775. doi:10.1016/j.expneurol.2011.11.036 PubMedCrossRefGoogle Scholar
  27. 27.
    Colle D, Hartwig JM, Soares FA, Farina M (2012) Probucol modulates oxidative stress and excitotoxicity in Huntington’s disease models in vitro. Brain Res Bull 87:397–405. doi:10.1016/j.brainresbull.2012.01.003 PubMedCrossRefGoogle Scholar
  28. 28.
    Farina M, Campos F, Vendrell I, Berenguer J, Barzi M, Pons S, Sunol C (2009) Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells. Toxicol Sci 112(2):416–426. doi:10.1093/toxsci/kfp219 PubMedCrossRefGoogle Scholar
  29. 29.
    Tanaka K, Ogawa N, Asanuma M (2006) Molecular basis of 6-hydroxydopamine-induced caspase activations due to increases in oxidative stress in the mouse striatum. Neurosci Lett 410(2):85–89. doi:10.1016/j.neulet.2006.08.021 PubMedCrossRefGoogle Scholar
  30. 30.
    Laursen SE, Belknap JK (1986) Intracerebroventricular injections in mice. Some methodological refinements. J Pharmacol Methods 16(4):355–357PubMedCrossRefGoogle Scholar
  31. 31.
    Prediger RD, Medeiros R, Pandolfo P, Duarte FS, Passos GF, Pesquero JB, Campos MM, Calixto JB, Takahashi RN (2008) Genetic deletion or antagonism of kinin B(1) and B(2) receptors improves cognitive deficits in a mouse model of Alzheimer’s disease. Neuroscience 151(3):631–643. doi:10.1016/j.neuroscience.2007.11.009 PubMedCrossRefGoogle Scholar
  32. 32.
    Moreira EL, Rial D, Duarte FS, de Carvalho CR, Horst H, Pizzolatti MG, Prediger RD, Ribeiro-do-Valle RM (2010) Central nervous system activity of the proanthocyanidin-rich fraction obtained from Croton celtidifolius in rats. J Pharm Pharmacol 62(8):1061–1068. doi:10.1111/j.2042-7158.2010.01124.x PubMedCrossRefGoogle Scholar
  33. 33.
    Carlberg I, Mannervik B (1985) Glutathione reductase. Methods Enzymol 113:484–490PubMedCrossRefGoogle Scholar
  34. 34.
    Wendel A (1981) Glutathione peroxidase. Methods Enzymol 77:325–333PubMedCrossRefGoogle Scholar
  35. 35.
    Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126PubMedCrossRefGoogle Scholar
  36. 36.
    Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247(10):3170–3175PubMedGoogle Scholar
  37. 37.
    Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358PubMedCrossRefGoogle Scholar
  38. 38.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  39. 39.
    Kostrzewa RM, Reader TA, Descarries L (1998) Serotonin neural adaptations to ontogenetic loss of dopamine neurons in rat brain. J Neurochem 70(3):889–898PubMedCrossRefGoogle Scholar
  40. 40.
    Reader TA, Dewar KM (1999) Effects of denervation and hyperinnervation on dopamine and serotonin systems in the rat neostriatum: implications for human Parkinson’s disease. Neurochem Int 34(1):1–21PubMedCrossRefGoogle Scholar
  41. 41.
    Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9(6):515–540PubMedCrossRefGoogle Scholar
  42. 42.
    Mates JM, Perez-Gomez C, Nunez de Castro I (1999) Antioxidant enzymes and human diseases. Clin Biochem 32(8):595–603PubMedCrossRefGoogle Scholar
  43. 43.
    Dringen R, Hirrlinger J (2003) Glutathione pathways in the brain. Biol Chem 384(4):505–516. doi:10.1515/BC.2003.059 PubMedCrossRefGoogle Scholar
  44. 44.
    Kumer SC, Vrana KE (1996) Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 67(2):443–462PubMedCrossRefGoogle Scholar
  45. 45.
    Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52(2):381–389PubMedCrossRefGoogle Scholar
  46. 46.
    Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69(3):1196–1203PubMedCrossRefGoogle Scholar
  47. 47.
    Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B (1997) A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental Lewy body disease. J Neurochem 69(3):1326–1329PubMedCrossRefGoogle Scholar
  48. 48.
    Floor E, Wetzel MG (1998) Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. J Neurochem 70(1):268–275PubMedCrossRefGoogle Scholar
  49. 49.
    Di Matteo V, Esposito E (2003) Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Curr Drug Targets CNS Neurol Disord 2(2):95–107PubMedCrossRefGoogle Scholar
  50. 50.
    Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2(5):325–334. doi:10.1038/35072550 PubMedCrossRefGoogle Scholar
  51. 51.
    Cohen G (1984) Oxy-radical toxicity in catecholamine neurons. Neurotoxicology 5(1):77–82PubMedGoogle Scholar
  52. 52.
    Soto-Otero R, Mendez-Alvarez E, Hermida-Ameijeiras A, Munoz-Patino AM, Labandeira-Garcia JL (2000) Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson’s disease. J Neurochem 74(4):1605–1612PubMedCrossRefGoogle Scholar
  53. 53.
    Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93PubMedGoogle Scholar
  54. 54.
    Dringen R (2005) Oxidative and antioxidative potential of brain microglial cells. Antioxid Redox Signal 7(9–10):1223–1233. doi:10.1089/ars.2005.7.1223 PubMedCrossRefGoogle Scholar
  55. 55.
    Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79(1–2):157–165. doi:10.1002/jnr.20280 PubMedCrossRefGoogle Scholar
  56. 56.
    Ghosh N, Ghosh R, Mandal SC (2011) Antioxidant protection: a promising therapeutic intervention in neurodegenerative disease. Free Radic Res 45(8):888–905. doi:10.3109/10715762.2011.574290 PubMedCrossRefGoogle Scholar
  57. 57.
    Baud O, Greene AE, Li J, Wang H, Volpe JJ, Rosenberg PA (2004) Glutathione peroxidase-catalase cooperativity is required for resistance to hydrogen peroxide by mature rat oligodendrocytes. J Neurosci 24(7):1531–1540. doi:10.1523/JNEUROSCI.3989-03.2004 PubMedCrossRefGoogle Scholar
  58. 58.
    Mozaffar S, Ueda M, Kitatsuji K, Shimizu S, Osumi M, Tanaka A (1986) Properties of catalase purified from a methanol-grown yeast, Kloeckera sp. 2201. Eur J Biochem 155(3):527–531PubMedCrossRefGoogle Scholar
  59. 59.
    Farina M, Frizzo ME, Soares FA, Schwalm FD, Dietrich MO, Zeni G, Rocha JB, Souza DO (2003) Ebselen protects against methylmercury-induced inhibition of glutamate uptake by cortical slices from adult mice. Toxicol Lett 144(3):351–357PubMedCrossRefGoogle Scholar
  60. 60.
    McCord JM, Fridovich I (1988) Superoxide dismutase: the first twenty years (1968–1988). Free Radic Biol Med 5(5–6):363–369PubMedCrossRefGoogle Scholar
  61. 61.
    Oh SH, Lim SC (2006) A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation. Toxicol Appl Pharmacol 212(3):212–223. doi:10.1016/j.taap.2005.07.018 PubMedCrossRefGoogle Scholar
  62. 62.
    Terland O, Flatmark T, Tangeras A, Gronberg M (1997) Dopamine oxidation generates an oxidative stress mediated by dopamine semiquinone and unrelated to reactive oxygen species. J Mol Cell Cardiol 29(6):1731–1738. doi:10.1006/jmcc.1997.0412 PubMedCrossRefGoogle Scholar
  63. 63.
    Bridges AB, Scott NA, Belch JJ (1991) Probucol, a superoxide free radical scavenger in vitro. Atherosclerosis 89(2–3):263–265PubMedCrossRefGoogle Scholar
  64. 64.
    Kalyanaraman B, Darley-Usmar VM, Wood J, Joseph J, Parthasarathy S (1992) Synergistic interaction between the probucol phenoxyl radical and ascorbic acid in inhibiting the oxidation of low density lipoprotein. J Biol Chem 267(10):6789–6795PubMedGoogle Scholar
  65. 65.
    Ebadi M, Sharma SK (2003) Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson’s disease. Antioxid Redox Signal 5(3):319–335. doi:10.1089/152308603322110896 PubMedCrossRefGoogle Scholar
  66. 66.
    Jenner P, Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47(6 Suppl 3):S161–S170PubMedCrossRefGoogle Scholar
  67. 67.
    Yamashita S, Matsuzawa Y (2009) Where are we with probucol: a new life for an old drug? Atherosclerosis 207(1):16–23. doi:10.1016/j.atherosclerosis.2009.04.002 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Renata Pietsch Ribeiro
    • 1
    • 2
    • 3
  • Eduardo Luiz Gasnhar Moreira
    • 1
    • 2
  • Danúbia Bonfanti Santos
    • 2
  • Dirleise Colle
    • 2
  • Alessandra Antunes dos Santos
    • 2
  • Kaite Cristiane Peres
    • 2
  • Claudia Pinto Figueiredo
    • 4
  • Marcelo Farina
    • 1
    • 2
  1. 1.Programa de Pós-Graduação em Neurociências, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  2. 2.Departamento de Bioquímica, Centro de Ciências BiológicasUniversidade Federal de Santa CatarinaFlorianópolisBrazil
  3. 3.Departamento Acadêmico de Saúde e ServiçoInstituto Federal de Santa CatarinaFlorianópolisBrazil
  4. 4.Departamento de Fármacos, Faculdade de Farmácia, Centro de Ciências da SaúdeUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil

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