Free radical scavenging properties of apomorphine enantiomers and dopamine: Possible implication in their mechanism of action in parkinsonism

  • E. E. Sam
  • N. Verbeke
Full Papers


The influence of R(-) apomorphine, S(+) apomorphine and deopamine on the oxidation kinetics of two polyunsaturated fatty acids (PUFA) (cholesteryl linoleate (CL) and Trilinolein (TL) was investigated The oxidation was initiated by free radicals generated through thermal decomposition of 2,2'-Azobis(2-methy-propionitrile) (AMPN) in phosphate buffer (pH 7.4) thermostated at 50°C. The hydroperoxides formed were determined by iodine titration using a diode array spectrophotometer at 290 nm.

Both enantiomers of apomorphine as well as dopamine exerted an inhibitory effect. Tocopherol (α-tocopherol) and ascorbic acid were used as controls. The former inhibited while ascorbic acid facilitated the oxidation reaction.

These results are discussed i relation with the possible role of oxidative injury in parkinsonism and the usefulness of apomorphine in elevating “on-off” episodes. On this basis, the non-dopaminergic enantiomer of apomorphine (S(+)-isomer) is put foward to test the importance of its radical scavenging properties in parkinsonism which could eventually lead to a therapeutic alternative with less side effects.

Key words

Apomorphine enantiomers free radicals radical scavenger dopamine α-tocopherol ascorbic acid parkinsonism 


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  1. Adam D, Odunze IN (1991) Oxygen free radicals: their involvement in disease processes. Ann Clin Biochem 27: 161–169Google Scholar
  2. Barbaeau A (1974) The clinical physiology of side effects in long term L-dopa therapy. Adv Neurol 5: 347–365Google Scholar
  3. Ben-Shachar D, Eshe G, Riederer P, Youdim MBH (1992) Role of iron and iron chelation in dopaminergic-induced neurodegeneration: implication in Parkinson's disease. Ann Neurol 32: s105-s110Google Scholar
  4. Biachi G, Landi M (1985) Determination of apomorphine in rat plasma and brain by highperfomance chromatography with electrochemical detection. J Chromatogr 338: 230–235Google Scholar
  5. Campbell A, Baldessarini R, Teicher M, Neumayer J (1985) σ(t)Apomorphins Selective inhibition of excitatory effects of dopamine injected to the limbic system of the rat. Neuropharmacol 24: 391–399Google Scholar
  6. Campbell A, Baldessarini R, Teicher M, Neumayer J (1986) Behavioral effects of apomorphine isomers in the rat: selective locomotor inhibitory effects of S(+)N-n-propylnorapomorphine. Psychopharmacol 88: 158–164Google Scholar
  7. Cebballos I, Lafon M, Javoy-Agid F, Hirsch E, Nicole A, Sinet PM, Agid Y (1990) Superoxide dismutase in parkinson's disease. Lancet 335: 1035–1036Google Scholar
  8. Cheknowa H, Costa LG, Woods JS, Castoldi A, Lund BO, Swanson PD (1992) Peripheral blood activities of monoamine oxidase B and superoxide dismutase in parkinson's disease. J Neural Transm [P-D Sect] 4: 283–290Google Scholar
  9. Chiueh CC, Miyake H, Peng MT (1993) Role of dopamine autoxidation, hydroxyl radical generation and calcium overload in underlying mechanisms involved in MPTP-induced parkinsonism. Adv Neurol 60: 251–258Google Scholar
  10. Cohen G (1990) Monoamine oxidase and oxidative stress at dopaminergic synapses. J Neural Transm [Suppl] 32: 229–238Google Scholar
  11. Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989a) Basal lipid peroxidation in substantia nigra is increased in parkinson's disease. J Neurochem 52: 381–389Google Scholar
  12. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD (1989b) Increased nigral iron content and alteration in other metals ions occurring in brain in parkinson's disease. J Neurochem 52: 1830–1836Google Scholar
  13. Elizan TS, Yahr MD, Moros DA, Mendoza MR, Pang S, Boodian CA (1989a) Selegline use to prevent progression of parkinson's disease. Experience in 22 de novo patients. Arch Neurol 46: 1275–1280Google Scholar
  14. Elizan TS, Yahr MD, Moros DA, Mendoza MR, Pang S, Bodian CA (1989b) Selegline as adjuvant in conventional levodopa therapy in parkinson's disease. Arch Neurol 46: 1280–1283Google Scholar
  15. Fischer PA, Baas H (1987) Therapeutic efficacy of (-)-deprenyl as adjuvant therapy in advanced parkinsonism. J Neural Transm 25 [Suppl]: 137–147Google Scholar
  16. Frankel JP, Lees AJ, Kempester PA, Stern GM (1990) Subcutaneous apomorphine in the treatment of parkinson's disease. J Neurol Neurosurg Psychiatry 53: 96–101Google Scholar
  17. Gancher ST, Woodward WR, Boucher B, Nutt JG (1989) Peripheral pharmacokinetic of apomorphine in humans. Ann Neurol 26: 232–238Google Scholar
  18. Graham GD, Tiffany SM, Bell WR, Gutknecht WF (1978) Autoxidation versus coval ent binding of ouinones as the mechanisms of toxicity of dopamine, 6-hydroxydop amie and elated compounds towards C1300 neuroblastoma cells in vivo. Mol Pharmacol 14: 644–653Google Scholar
  19. Halliwell B (1989) Oxidant and the central nervous system: some fundamental questions. Acta Neurol Scand 126: 23–33Google Scholar
  20. Hesagawa E, Takeshije K, Oishi T, Murai Y, Minakami S (1990) 1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart mitochondrial particles. Biochem Biophys Res Commun 170: 1049–1055Google Scholar
  21. Hicks M, Gebicki JM (1979) A spectrophotometric method for determination of lipid hydroperoxides. Anal Biochem 99: 249–253Google Scholar
  22. Hofstee DJ, Neef C, van Laar T, Jansen ENH (1994) Pharmacokinetics of apomorphine in parkinson's disease: plasma and cerebrospinal fluid levels in relation to motor responces. Clin Neuropharmacol 17: 45–52Google Scholar
  23. Kebabian JW (1978) A sensitive enzymatic radioisotopic assay for apomorphine. J Neurochem 30: 114–144Google Scholar
  24. Lee T, Seeman P, Rajput A, Ferley IJ, Hornykiewicz O (1978) Receptor basis for dopaminegic supersensitivity in parkinson's disease. Nature 273: 5961Google Scholar
  25. Liu J, Mori A (1993) Monoamine metabolism provides antioxidant defence in the brain against oxidant and free radical induced damage. Arch Biochem Biophys 302: 118–127Google Scholar
  26. Mally J (1992) Some new aspects of the effects of deprenyl in parkinson's disease: retrospective study. J Neural Transm [P-D Sec] 4: 155–164Google Scholar
  27. Marsden CD, Parkes JD (1976) “On-off” effects in patients with parkinson's disease on chronic levodopa therapy. Lancet i: 292–296Google Scholar
  28. Montastruc JL, Rascol O, Gerald GM, Gualano V, Bagheri H (1991) Sublingual apomorphine in parkinson's diseae: a clinical and pharmacokinetic study. Clin Neuropharmacol 14: 432–437Google Scholar
  29. Niki E (1991) Action of ascorbic acid as a scvenger of active and stable oxygen radicals. Am J Clin Nutr 54: 1119S-1124SGoogle Scholar
  30. Obeso JA Grandas F, Vaamonde J, Luquin MR, Martinez-Lage JM (1987) Apomorphine infusion for motor fluctuations in parkinsons disease. Lancet i: 1376–1377Google Scholar
  31. Parkinson Study Group (1993) Effects of tocopherol and deprenyl on the progression of disability in early parkinsons's disease. N Engl J Med 328: 176–183Google Scholar
  32. Poewe W, Gerstenbrand F, Ransmayr G (1987) Experience with selegline in the treatment of parkinson's disease. J Neural Transm 25 [Suppl]: 147–150Google Scholar
  33. Poewe W, Kleedorfer B, Gerstenbrand F, Oertel W (1988) Subcutaneous apomorphine in parkinsons disease. Lancet i: 1943Google Scholar
  34. Przedborski S, Kostic V, Jackson-Lewis V, Naini AB, Simonetti S, Fahn S, Carlson E, Epstein CJ, Cadet JL (1992) Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced neurotoxicity. Neurosci 12: 1658–1667Google Scholar
  35. Przedborski S, Levivier M, Paftopoulos C, Naini AB, Hildebrand J (1995) Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans. Mov Disord 10: 28–36Google Scholar
  36. Riederer P, Sofic E, Rausch W, 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
  37. Saggu H, Cooksey J, Dexter D, Wells FR, Lees A, Jenner P, Marsden CD (1989) A selective increase in particulate superoxide activity in parkinsonian substanta nigra. J Neurochem 53: 692–697Google Scholar
  38. Sam E, Augustijns P, Verbeke N (1994) Stability of apomorphine in plasma and its determination by high-performance liquid chromatography with electrochemical detection. J Chromatogr B 658: 311–317Google Scholar
  39. Sam E, Jeanjean AP, Maloteaux JM, Verbeke N (1995) Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application. Eur J Drug Met Pharmacokin 20: 27–33Google Scholar
  40. Seeman P, Van Tol HH (1993) Dopamine D-4 receptors bind inactive (+) aporphin es suggesting neuroleptic role. Sulpride not stereoselective. Eur J Pharmacol 233: 73–174Google Scholar
  41. Shaw KM, Lees AJ, Stern GM (1980) The impact of treatment with levedopa in parkinson's disease. Q j Med 49: 283–293Google Scholar
  42. Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MDH (1991) Selective increase in iron in substantia nigra zona compacta in parkinsonian brain. J Neurochem 56: 978–982Google Scholar
  43. Steiger JM, Quinn NP, Marsden CD (1992) The clinical use of apomorphine in parkinson's disease. J Neurol 239: 389–393Google Scholar
  44. Stibbe C, Lees A, Stern G (1987) Subcutaneous infusion of apomorphine and lisuride in the treatment of “on-off” fluctuations. Lancet ii: 871Google Scholar
  45. Stibbe CMH, Kempester PA, Lees AJ, Stern GM (1988) Subcutaneous apomorphine in parkinsonian “on-off” oscillations. Lancet i: 403–406Google Scholar
  46. Ubeda A (1993) Iron reducing and free radical scavenging properties of apomorphine and some related bezylisoquinolines. Free Radic Biol Med 15: 159–167Google Scholar
  47. Van Tol HHM, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D-4 receptor with high affinity for antipsychotic clozapine. Nature 350: 310Google Scholar
  48. Westerink BHC, Horn AS (1979) D neuroleptics prevent the penetration of dopamine agonists into the brain? Eur J Pharmacol 58: 39–48Google Scholar
  49. Yamamoto Y, Niki E, Kamiya Y, Shimasaki H (1984) Oxidation of phosphatidylcholine in homogenous solution and in water dispersion. Biochim Biophys Acta 795: 323–340Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • E. E. Sam
    • 1
  • N. Verbeke
    • 1
  1. 1.Labroatorium voor Galenische en Klinische FarmacieKatholieke Universiteit LeuvenLeuvenBelgium

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