Journal of Neurology

, Volume 239, Supplement 1, pp S2–S8 | Cite as

Parkinson's disease: pathological mechanisms and actions of piribedil

  • Peter Jenner


The cause of the degeneration of dopamine-containing cells in the zona compacta of the substantia nigra in Parkinson's disease remains unknown. The ability of the selective nigral toxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) (via its metabolite MPP+) to destroy nigral dopamine cells selectively by inhibiting complex I of the mitochondrial energy chain may provide a clue. Indeed, recent studies of post-mortem brain tissue have suggested the presence of an on-going toxic process in the substantia nigra in Parkinson's disease leading to excess lipid peroxidation. This appears also to involve a disruption of mitochondrial function since mitochondrial superoxide dismutase activity is increased and there is impairment of complex I. These changes may in turn relate to a selective increase in the total iron content of substantia nigra coupled to a generalised decrease in brain ferritin content. Piribedil is used in the symptomatic treatment of Parkinson's disease and is particularly effective against tremor. Piribedil (and its metabolites) acts as a dopamine D-2 receptor agonist. However, in our studies in contrast to other dopamine agonists, in vivo piribedil interacts with dopamine receptors in the substantia nigra and nucleus accumbens but not those in the striatum. In patients with Parkinson's disease the beneficial effects of piribedil may be limited by nausea and drowsiness. Indeed, in MPTP-treated primates piribedil reverses motor deficits but marked side-effects occur. However, pre-treatment with the peripheral dopamine receptor antagonist domperidone prevents the unwanted effects and piribedil produces a profound and longer-lasting reversal of all components of the motor syndrome. These results suggest that combined with domperidone piribedil could be used as an effective monotherapy in the treatment of Parkinson's disease.

Key words

Parkinson's disease Post-mortem studies Mitochondrial impairment Piribedil MPTP 


  1. 1.
    Agid Y, Javoy-Agid F (1985) Peptides and Parkinson's disease. Trends Neurosci 7:30–35Google Scholar
  2. 2.
    Agid Y, Javoy-Agid F, Ruberg M (1987) Biochemistry of neurotransmitters in parkinson's disease. In: Marsden CD, Fahn S (eds) Neurology 2: Movement disorders. Butterworth, London, pp 166–230Google Scholar
  3. 3.
    Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destructin of dopaminergic neurons in the pars compacta of the substantia nigra byN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 80:4546–4550Google Scholar
  4. 4.
    Corrodi H, Fuxe K, Ungerstedt U (1971) Evidence for a new type of dopamine receptor stimulating agent. J Pharm Pharmacol 23:989–991Google Scholar
  5. 5.
    Corrodi H, Farnebo LO, Fuxe K (1972) ET 495 and brain catecholamine mechanisms: evidence for stimulation of dopamine receptors. Eur J Pharmacol 20:195–204Google Scholar
  6. 6.
    Costall B, Naylor RJ (1973) The site and mode of action of ET 495 for the mediation of stereotyped behaviour in the rat. Naunyn Schmiedebergs Arch Pharmacol 278:117–133Google Scholar
  7. 7.
    Costall B, Naylor RJ (1975) Actions of dopaminergic agonists on motor function. Adv Neurol 9:285–297Google Scholar
  8. 8.
    Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IP (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1:249–254Google Scholar
  9. 9.
    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 52:381–389Google Scholar
  10. 10.
    Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J Neurochem 52:1830–1836Google Scholar
  11. 11.
    Dexter DT, Carayon A, Vidailhet M, Ruberg M, Agid F, Agid Y, Lees AJ, Wells FR, Jenner P, Marsden CD (1990) Decreased ferritin levels in brain in Parkinson's disease. J Neurochem 55:16–20Google Scholar
  12. 12.
    Dexter DT, Carayon A, Javoy-Agid, Agid Y, Wells FR, Daniel SE, Lees AJ, Jenner P, Marsden CD (1991) Alterations in the levels of iron and ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114:1953–1975Google Scholar
  13. 13.
    Earle KM (1968) Studies in Parkinson's disease including Xray fluorescent spectroscopy of formalin-fixed tissue. J Neuropathol Exp Neurol 27:1–14Google Scholar
  14. 14.
    Forno LS (1981) Pathology of Parkinson's disease. In: Marsden CD, Fahn S (eds) Neurology 2: Movement disorders. Butterworth, London, pp 25–40Google Scholar
  15. 15.
    Goldstein M, Battista A, Ohmoto T, Anagnoste B, Fuxe K (1973) Tremor and involuntary movements in monkeys: effect ofl-DOPA and of a dopamine receptor stimulating agent. Science 179:816–817Google Scholar
  16. 16.
    Hall MD, Jenner P, Marsden CD (1983) Differential labelling of dopamine receptors in rat brain in vivo: comparison of3H-piribedil,3H-S 3608 and3H-N,n-propyl norapomorphine. Eur J Pharmacol 87:85–94Google Scholar
  17. 17.
    Hornykiewicz O (1981) Brain neurotransmitter changes in Parkinson's disease. In: Marsden CD, Fahn S (eds) Neurology 2: Movement disorders. Butterworth, London, pp 41–48Google Scholar
  18. 18.
    Jenner P (1990) Parkinson's disease: clues to the cause of cell death in the substantia nigra. Semin Neurosci 2:117–126Google Scholar
  19. 19.
    Jenner P, Taylor AR, Campbell DB (1973) Preliminary investigation of the metabolism of piribedil (ET495); a new central dopaminergic agonist and potential antiparkinsonian agent. J Pharm Pharmacol 25:749–750Google Scholar
  20. 20.
    Jenner P, Rupniak NMJ, Rose S, Kelly E, Kilpatrick G, Lees A, Marsden CD (1984) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset. Neurosci Lett 50:85–90Google Scholar
  21. 21.
    Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonsim in humans due to a product of meperidine-analog synthesis. Science 219:979–980Google Scholar
  22. 22.
    Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in squirrel monkeys. Brain Res 292:390–394Google Scholar
  23. 23.
    Lieberman AN, Shopsin B, Le Brun Y, Boal D, Zolfaghari M (1975) Studies in piribedil in parkinsonism. Neurol 9:399–407Google Scholar
  24. 24.
    Loeschmann P-A, Chong PN, Nomoto M, Tepper PG, Horn AS, Jenner P, Marsden CD (1989) Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437. Eur J Pharmacol 166:373–380Google Scholar
  25. 25.
    Marttilla RJ, Lorentz H, Rinne UK (1988) Oxygen toxicity protecting enzymes in Parkinson's disease. Increase of superoxide dismutase-like activity in the substantia nigra and basal nucleus. J Neurol Sci 86:321–331Google Scholar
  26. 26.
    McGeer PLK, Itagaki S, Akiyama H, McGeer EG (1989) Comparison of neuronal loss in Parkinson's disease and aging. In: Calne DB, Comi G, Crippa D, Horowski R, Trabucchi M (eds) Parkinsonism and aging. Raven Press, New York, pp 25–34Google Scholar
  27. 27.
    Miller RJ, Iversen LL (1974) Stimulation of a dopamine sensitive adenylate cyclase in homogenates of rat striatum by a metabolite of piribedil (ET 495). Naunyn Schmiedebergs Arch Pharmacol 282:213–216Google Scholar
  28. 28.
    Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sata T, Oya H, Ozawa T, Kagawa Y (1989) Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun 163:1450–1455Google Scholar
  29. 29.
    Neafsey EJ, Drucker G, Raikoff K, Collins MA (1989) Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a B-carbolinium analog ofn-methyl-4-phenylpyridinium ion (MPP+). Neurosci Lett 105:344–349Google Scholar
  30. 30.
    Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADHlinked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Life Sci 36:2503–2508Google Scholar
  31. 31.
    Nomoto N, Stahl S, Jenner P, Marsden CD (1987) Antiparkinsonian activity of (+)-PHNO in the MPTP-treated common marmoset. Mov Disord 2:37–45Google Scholar
  32. 32.
    Ogatawa M, Araki M, Nagatsu I, Nagatsu T, Yoshida M (1989) The effect of 1,2,3,4-tetrahydroisoquinoline (TIQ) on mesencephalic dopaminergic neurons in C57BL/6J mice: immunohistochemical studies — tyrosine hydroxylase. Biogenic Amines 6:427–436Google Scholar
  33. 33.
    Olanow CW, Holgate RC, Murtaugh R, Martinez C (1989) MR imaging in Parkinson's disease and aging. In: Calne B, Comi G, Crippa D, Trabucchi M (eds) Parkinsonism and aging. Raven Press, New York, pp 155–164Google Scholar
  34. 34.
    Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 26:719–723Google Scholar
  35. 35.
    Parkinson's Disease Study Group (1989) Effects of deprenyl on the progression of disability in early Parkinson's disease. New Engl J Med 321:1364–1371Google Scholar
  36. 36.
    Poignant J-C, Laubie M, Tseoris-Kupper D, Schmitt H (1972) Action de divers réactifs pharmacologiques sur les mouvements stéréotypés produits chez le rat par l'ingestion de 1-(2″ pyrimidyl-4-piperoxyl) piperazine (piribedil). C R Acad Sci 275:715–717Google Scholar
  37. 37.
    Poignant J-C, Lejeune F, Malecot E, Petitjean M, Regnier G, Canevari R (1974) Effects comparés du piribedil et de trois de ses métabolites sur le système extrapyramidal du rat. Experientia 30:70Google Scholar
  38. 38.
    Reavill C, Jenner P, Marsden CD (1983) Differentiation of dopamine agonists using drug-induced rotation in rats with unilateral or bilateral 6-hydroxydopamine destruction of ascending dopamine pathways. Biochem Pharmacol 32:865–870Google Scholar
  39. 39.
    Riederer P, Sofic E, Rausch W-D, Schmidt B, Reynolds GP, Jellinger K, Youdim MBH (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52:515–520Google Scholar
  40. 40.
    Rondot P, Bathien N, Ribadeau Dumas JL (1975) Indications of piribedil in L-DOPA-treated parkinsonian patients: physiopathologic implications. Adv Neurol 9:373–381Google Scholar
  41. 41.
    Rossetti ZL, Sotigui A, Sharp DE, Hadjiconstantinou M, Neff NH (1988) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro. Biochem Pharmacol 37:4573–4574Google Scholar
  42. 42.
    Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, Dureux R, Hauw J-J, Duyckaerts C, Gray F, Morel-Maroger A, Rascol A, Serdaru M, Agid Y (1985) Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann Neurol 18:523–529Google Scholar
  43. 43.
    Saggu H, Cooksey J, Dexter D, Wells FR, Lees A, Jenner P, Marsden CD (1989) A selective increase in particulate superoxide dismutase activity in parkinsonian substantia nigra. J Neurochem 53:692–697Google Scholar
  44. 44.
    Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 54:820–827Google Scholar
  45. 45.
    Schapira AHV, Mann VM, Cooper JM, Dexter D, Daniel SE, Jenner P, Clark JB, Marsden CD (1990) Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson's disease. J Neurochem 55:2142–2145Google Scholar
  46. 46.
    Sofic E, Riederer P, Heinsen H, Beckman H, Reynolds GP, Hebenstrett G, Youdim MBH (1988) Increased iron (III) and total iron content in post-mortem substantia nigra of parkinsonian brain. J Neural Transm 74:199–205Google Scholar
  47. 47.
    Steventon GB, Heafield MTE, Waring RH, Williams AC (1989) Xenobiotic metabolism in Parkinson's disease. Neurology 39:883–887Google Scholar
  48. 48.
    Tanner CM (1989) The role of environmental toxins in the etiology of Parkinson's disease. Trends Neurosci 12:49–54Google Scholar
  49. 49.
    Vyas I, Heikkila RE, Nicklas WJ (1986) Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: inhibition of NAD-linked substrate oxidation by its metabolite, 1-methyl-4-phenylpyridinium. J Neurochem 46:1501–1507Google Scholar
  50. 50.
    Waring RH, Sturman SG, Smith MCG, Steventon GB, Heafield MTE, Williams AC (1989) S-methylation in motorneurone disease and Parkinson's disease. Lancet II:356–357Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Peter Jenner
    • 1
  1. 1.Parkinson's Disease Society Experimental Research Laboratories, Pharmacology Group, Biomedical Sciences DivisionKing's College LondonLondonUK

Personalised recommendations