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Increased plasma bilirubin in Parkinson patients on L-dopa: evidence against the free radical hypothesis?

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Abstract

Oxidative damage by free radicals may contribute to the etiology of Parkinson's disease (PD), and increased oxidative stress in the nigral cells of PD patients may occur following L-dopa treatment, prompting suggestions that L-dopa therapy should be delayed as long as possible. Bilirubin is a potent antioxidantin vitro, even when bound to albumin, suggesting a physiological role as an antioxidant. Calculations indicate that bilirubin can pass the blood-brain barrier in sufficient quantity to exert a significant antioxidant effect in the brain. We have found a highly significant (about 20%) increase in plasma bilirubin in 162 PD patients on chronic L-dopa treatment compared to 93 untreated parkinsonians and 224 non-parkinsonian controls. We propose that L-dopa-induced increase in nigral oxidative stress in PD may be effectively counteracted by increased bilirubin levels. The mechanism by which plasma bilirubin is increased in patients receiving L-dopa is at present unknown.

Sommario

Il danno ossidativo prodotto dai radicali liberi può contribuire a provocare il morbo di Parkinson (PD), inoltre il trattamento con L-dopa può determinare un aumento dello stress ossidativo nelle cellule nigrali dei pazienti con PD e questo suggerirebbe di ritardare il più a lungo possibile la terapia con L-dopa. La bilirubina è un potente antiossidantein vitro anche quando è legata all'albumina e questo propone un suo ruolo fisiologico come agente antiossidante. È stato calcolato che la bilirubina è in grado di attraversare la barriera emato-encefalica in quantità sufficienti da esercitare un effetto antiossidante nel cervello. Abbiamo trovato un aumento significativo (circa del 20%) della bilirubina plasmatica in 162 pazienti con PD in trattamento cronico con L-dopa in confronto a 93 pazienti parkinsoniani non trattati e 224 soggetti di controllo non parkinsoniani. Proponiamo che lo stress ossidativo nelle cellule nigrali prodotto dalla L-dopa nei pazienti parkinsoniani possa essere efficacemente controbilanciato da livelli aumentati di bilirubina. Il meccanismo con il quale la bilirubina plasmatica viene aumentata non è attualmente conosciuto.

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References

  1. Ames BN.Dietary carcinogens and anticarcinogens, oxygen free radicals and degenerative diseases. Science 1983; 221: 1256–1264.

    PubMed  CAS  Google Scholar 

  2. Ames BN, Cathcart R, Schwiers E, Hochstein P.Uric acid provides an antioxidant defense in humans against oxidant and radical-caused aging and cancer. A hypothesis. Proc Nat Acad Sci USA 1981; 78: 6858–6862.

    PubMed  CAS  Google Scholar 

  3. Burton GW, Ingold KV.β-carotene: an unusual type of lipid antioxidant. Science 1984; 224: 569–573.

    PubMed  CAS  Google Scholar 

  4. Cerutti PA.Prooxidant states and tumor promotion. Science 1985; 227: 375–381.

    PubMed  CAS  Google Scholar 

  5. Clhoun WJ, Reed HE, Moest DR, Stevens CA.Enhanced superoxide production by alveolar macrophages and air-space cells, airway inflammation and alveolar macrophage density changes after segmental antigen bronchoprovocation in allergic subjects. Am Rev Respir Dis 1992; 145: 317–325.

    PubMed  Google Scholar 

  6. Comporti M.Lipid peroxidation and cell damage in toxic liver injury. Lab Invest 1985; 53: 599–623.

    PubMed  CAS  Google Scholar 

  7. Cotzias GC, Miller ST, Nicholson AR Jr, et al.:Prolongation of the life span in mice adapted to large amounts of L-dopa. Proc Nat Acad Sci USA 1974; 71(6): 2466–2469.

    PubMed  CAS  Google Scholar 

  8. Davis GC, Williams AC, Markey SP, et al.:Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979; 1: 649–654.

    Google Scholar 

  9. Diamond SG, Markham CH, Hoehn MM.Multi-center study of Parkinson mortality with early versus later L-dopa treatment. Ann Neurol 1987; 22: 8–12.

    Article  PubMed  CAS  Google Scholar 

  10. Halliwell B andGutteridge JMC.Oxygen radicals and the nervous system. Trends Neurosci 1985; 8: 22–26.

    Article  CAS  Google Scholar 

  11. Halliwell B, Gutteridge MC.Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 1984; 219: 1–14.

    PubMed  CAS  Google Scholar 

  12. Halliwell B.Free radicals, antioxidants and human disease: curiosity, cause or consequence? The Lancet 1994; 42: 2241–2250.

    Google Scholar 

  13. Hoehn MM.Parkinson's disease: progression and mortality. In: Yahr MD, Bergmann KJ, eds. Advances in Neurology. New York: Raven Press 1986; 45: 457–461.

    Google Scholar 

  14. Jenner P.Oxidative damage in neurodegenerative disease. The Lancet 1994; 17: 796–798.

    Article  Google Scholar 

  15. Jenner P, Schapira AHV, Marsden CD.New insights into the cause of Parkinson's disease. Neurology 1992; 42: 2241–2250.

    PubMed  CAS  Google Scholar 

  16. Kanazawa H, Kurihara N, Hirata K, Takeda T.The role of free radicals in airway obstruction in asthmatic patients. Chest 1991; 100: 1319–1322.

    PubMed  CAS  Google Scholar 

  17. Kopin IJ, Markey SP, Burns RS, Johannessen JN, Chiueh CC.Mechanisms of neurotoxicity of MPTP. In: S. Fahn et al. eds. Recent Developments in Parkinson's Disease. New York: Raven Press 1986; 165–173.

    Google Scholar 

  18. Langston JW, Ballard P, Tetrud JW, Irwin I.Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 219: 979–980.

    PubMed  CAS  Google Scholar 

  19. Levine RL.Bilirubin: worked out years ago? Pediatrics 1979; 64: 380–385.

    PubMed  CAS  Google Scholar 

  20. Liu K, Cuddy TE, Pierce GN.Oxidative status of lipoproteins in coronary disease patients. Am Heart J 1992; 123: 285–290.

    Article  PubMed  CAS  Google Scholar 

  21. Lyons TJ.Oxidized low density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes? Diab Med 1991; 8: 411–419.

    Article  CAS  Google Scholar 

  22. Matsushita S, Ibuki F, Aoki A.Chemical reactivity of the nuclei acid bases. I. Antioxidative ability of the nuclei acids and their related substances on the oxidation of unsaturated fatty acids. Arch Biochem Biophys. 1963; 102: 446–451.

    Article  PubMed  CAS  Google Scholar 

  23. Melamed E.Initiation of levodopa therapy in parkinsonian patients should be delayed until the advanced stages of the disease. Arch Neurol 1986; 43: 402–405.

    PubMed  CAS  Google Scholar 

  24. Mena MA, Pardo B, Casarejos MJ, et al.:Neurotoxicity of levodopa on catecholamine rich neurons. Mov Disord 1992; 7: 23–31.

    Article  PubMed  CAS  Google Scholar 

  25. Nakazono K, Watanabe N, Matsuno K, Sasaki J, Sato M, Inoue M.Does superoxide underlie the pathogenesis of hypertension? Proc Nat Acad Sci USA 1991; 88: 10045–10048.

    PubMed  CAS  Google Scholar 

  26. Quinn N, Parkes D, Janota I, Marsden CD.Case report: preservation of the substania nigra and locus coeruleus in a patient receiving levodopa (2g) plus decarboxylase inhibitor over a four year period. Move Disord 1986; 1(1): 65–68.

    Article  CAS  Google Scholar 

  27. Robinson PJ, Rapoport SI.Kinetics of protein binding determine rates of uptake of drugs by brain. Am J Physiol 1986; 251: 1212–1220.

    Google Scholar 

  28. Robinson PJ, Rapoport SI.Binding effect of bilirubin on uptake of bilirubin by brain. Pediatrics 1987; 79(4): 553–558.

    PubMed  CAS  Google Scholar 

  29. Scigliano G, Musicco M, Soliveri P, et al.:Mortality associated with early and late therapy initiation in Parkinson's disease. Neurology 1990; 40: 265–269.

    Article  PubMed  CAS  Google Scholar 

  30. Sedghi S, Fields JZ, Klamut M, et al.:Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis. Gut 1993; 34: 1181–1197.

    Google Scholar 

  31. Stocker R, Glazer AN, Ames BN.Antioxidant activity of albumin-bound bilirubin. Proc Nat Acad Sci USA 1987; 84: 5918–5922

    PubMed  CAS  Google Scholar 

  32. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN.Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043–1046.

    PubMed  CAS  Google Scholar 

  33. Suarez M, Beloqui O, Ferrer JV, et al.:Glutathione depletion in chronic hepatitis. C Ing Hepatol Commun 1993; 1: 215–221.

    Google Scholar 

  34. Totter JR.Spontaneous cancer and its possible relationships to oxygen metabolism. Proc Nat Acad Sci USA 1980; 77: 1763–1767.

    PubMed  CAS  Google Scholar 

  35. Uitti RJ, Ahlskong JE, Maraganore DM, et al.:Levodopa therapy and survival in idiopathic Parkinson's disease: Olmsted County Project. Neurology 1993; 43: 1918–1926.

    PubMed  CAS  Google Scholar 

  36. Wright CE, Tallan HH, Lin YY.Taurine: biological update. Ann Rev Biochem 1986; 55: 427–453.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Istituto di Tecnologie Biomediche Avanzate, CNR, Milano, Italy

    Musicco M. & Radice D.

  2. Istituto Nazionale Neurologico “C. Besta”, Via Celoria, 20133, Milano, Italy

    Scigliano G., Girotti F., Soliveri P., Musicco M., Radice D. & Caraceni T.

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  1. Scigliano G.
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  2. Girotti F.
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  3. Soliveri P.
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  4. Musicco M.
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  5. Radice D.
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  6. Caraceni T.
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Scigliano, G., Girotti, F., Soliveri, P. et al. Increased plasma bilirubin in Parkinson patients on L-dopa: evidence against the free radical hypothesis?. Ital J Neuro Sci 18, 69–72 (1997). https://doi.org/10.1007/BF01999565

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  • DOI: https://doi.org/10.1007/BF01999565

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