Journal of Neural Transmission

, Volume 104, Issue 2–3, pp 209–228

Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole

  • P. M. Carvey
  • S. Pieri
  • Z. D. Ling
Parkinson's Disease and Allied Conditions


The direct-acting dopamine (DA) agonist pramipexole (2 amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrocfiloride) was evaluated for its ability to attenuate levodopa-induced loss of tyrosine hydroxylase immunoreactive (THir, a marker for dopamine neurons) cells in mesencephalic cultures. Pramipexole reduced levodopa-induced THir cell loss in a dosedependent and saturable fashion (ED50=500 pM), its inactive stereoisomer was significantly less potent in this regard and pergolide and bromocriptine had negligible cytoprotective effects. Culture media from mesencephalic cultures incubated with pramipexole for 6 days increased THir cell counts in freshly harvested recipient cultures. The magnitude of this effect was directly proportional to the amount of pramipexole in the donor cultures and heatinactivation of the media abolished the growth promoting effect. The results from this exploratory set of experiments suggest that pramipexole may be cytoprotective to dopamine neurons in tissue culture. Pramipexole's affinity for DA receptors, its antioxidant action or its ability to enhance mesencephalic trophic activity could be responsible for this effect.


Pramipexole mesencephalic cultures levodopa toxicity pergolide bromocriptine trophic factor oxidant stress neuroprotection 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams JD, Odunze IN (1991) Oxygen free radicals and Parkinson's disease. Free Radic Biol Med 10: 161–169PubMedGoogle Scholar
  2. Althaus JS, Fici GJ, Von Voigtlander PF (1996) The dopamine agonist pramipexole blocks the oxidative toxicity of L-DOPA in culture. Soc Neurosci Abstr 22: 219Google Scholar
  3. Baczynskyj L, Althaus JS, VonVoigtlander PF (1996) Electrochemical oxidation of pramipexole. 44th ASMS Conference on Mass Spectrometry and Allied TopicsGoogle Scholar
  4. Blunt SB, Jenner P, Marsden CD (1991) The effect of L-dopa and carbidopa treatment on the survival of rat fetal dopamine grafts assessed by tyrosine hydroxylase immunohistochemistry and [3H]mazindol autoradiography. Neuroscience 43: 95–110PubMedGoogle Scholar
  5. Blunt SB, Jenner P, Marsden CD (1993) Suppressive effect of L-dopa on dopamine cells remaining in the ventral tegmental area of rats previously exposed to the neurotoxin 6-hydroxydopamine. Mov Disord 8: 129–133PubMedGoogle Scholar
  6. Brundin P, Isacson O, Bjorklund A (1985) Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res 331: 251–259PubMedGoogle Scholar
  7. Calne DB, Zigmond MJ (1991) Compensatory mechanisms in degenerative neurologic diseases. Insights from parkinsonism. Arch Neurol 48: 361–363PubMedGoogle Scholar
  8. Camacho-Ochoa M, Walker EL, Evans DL, Piercey MF (1995) Rat brain binding sites for pramipexole, a clinically useful D3-preferring dopamine agonist. Neurosci Lett 196: 97–100PubMedGoogle Scholar
  9. Carter AJ, Muller RE (1991) Pramipexole, a dopamine D2 autoreceptor agonist, decreases the extracellular concentration of dopamine in vivo. Eur J Pharmacol 200: 65–72Google Scholar
  10. Carvey PM, Ptak LR, Lo ES, Lin DH, Buhrfiend CM, Goetz CG, Klawans HL (1991) Levodopa reduces the growth promoting effects of striatal extracts on rostral mesencephalic tegmentum cultures. Exp Neurol 114: 28–34PubMedGoogle Scholar
  11. Carvey PM, Ptak LR, Lin D, Lo ES, Buhrfiend CM, Drucker GE, Fields JZ (1993) Alterations in striatal neurotrophic activity induced by dopaminergic drugs. Pharmacol Biochem Behav 46: 195–204PubMedGoogle Scholar
  12. Dal Toso R, Giorgi O, Soranzo C, Kirschner G, Ferrari G, Favaron M, Benvegnu D, Presti D, Vicini S, Toffano G (1988) Development and survival of neurons in dissociated fetal mesencephalic serum-free cell cultures I. Effects of cell density and of an adult mammalian striatal-derived neuronotrophic factor (SDNF). J Neurosci 8: 733–745PubMedGoogle Scholar
  13. 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: 381–389PubMedGoogle Scholar
  14. Felten DL, Felten SY, Fuller RW, Romano TD, Smalstig EB, Wong DT, Clemens JA (1992) Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-Fischer-344 rats. Neurobiol Aging 13: 339–351PubMedGoogle Scholar
  15. Fornstedt B, Brun A, Rosengren E, Carlsson A (1989b) The apparent autoxidation rate of catechols in dopamine-rich regions of human brains increases with the degree of depigmentation of substantia nigra. J Neural Transm [PD Sect] 1: 279–295Google Scholar
  16. Goldstein M, Lew JY, Sauter A, Lieberman A (1980a) The affinities of ergot compounds for dopamine agonist and dopamine antagonist receptor sites. Adv Biochem Psychopharmacol 23: 75–82PubMedGoogle Scholar
  17. Goldstein M, Lieberman A, Lew JY, Asano T, Rosenfeld MR, Makman MH (1980b) Interaction of pergolide with central dopaminergic receptors. Proc Natl Acad Sci USA 77: 3725–3728PubMedGoogle Scholar
  18. Graham DG, Tiffany SM, Bell WR, 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: 644–653PubMedGoogle Scholar
  19. Hall ED, Andrus PK, Oostveen JA, Althaus JS, VonVoigtlander PF (1996) Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons. Brain Res (in press)Google Scholar
  20. Hefti F, Melamed E, Bhawan J, Wurtman RJ (1981) Long-term administration of L-DOPA does not damage dopaminergic neurons in the mouse. Neurology 31: 1194–1195Google Scholar
  21. Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson's disease. Adv Neurol 45: 19–34PubMedGoogle Scholar
  22. Hubble JP, Koller WC, Cutler N, Friedman J, Goetz CG, Ranhosky A, Korts D, Elvin A (1995) Pramipexole, a highly selective dopamine agonist in patients with early Parkinson's disease: an ascending-dose trial. Clin Neuropharmacol 18: 338–347PubMedGoogle Scholar
  23. Jenner P (1995) The rationale for the use of dopamine agonists in Parkinson's disease. Neurology 45: S6–12Google Scholar
  24. Kontur PJ, Marek K, Roth R, Redmond DE (1993) Effects of L-dopa and dopamine receptor agonists on cultured rat mesencephalic dopamine neurons. Neurology 43: A153Google Scholar
  25. Ling ZD, Pieri S, Carvey PM (1996) Comparison of the neurotoxicity of dopa stereoisomers in cultured dopamine neurons. Clin Neuropharmacol 4: 360–365Google Scholar
  26. Loeffler DA, DeMaggio AJ, Juneau PL, Havaich MK, LeWitt PA (1994) Effects of enhanced striatal dopamine turnover in vivo on glutathione oxidation. Clin Neuropharmacol 17: 370–379PubMedGoogle Scholar
  27. Mena MA, Pardo B, Casarejos MJ, Fahn S, de Yebenes JG (1992) Neurotoxicity of levodopa on catecholamine-rich neurons. Mov Disord 7: 23–31PubMedGoogle Scholar
  28. Michel PP, Hefti F (1990) Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture. J Neurosci Res 26: 428–435PubMedGoogle Scholar
  29. Mierau J (1995) Pramipexole: a dopamine-receptor agonist for treatment of Parkinson's disease. Clin Neuropharmacol 18 [Suppl 1]: S195-S206Google Scholar
  30. Mierau J, Bechtel WD (1988) SND 919 inhibits dopamine release in vivo and in vitro (abstract). Psychopharmacology 96: 338Google Scholar
  31. Mierau J, Schingnitz G (1992) Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist. Eur J Pharmacol 215: 161–170PubMedGoogle Scholar
  32. Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM (1995) Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors. Eur J Pharmacol 290: 29–36PubMedGoogle Scholar
  33. Mons N, Tison F, Geffard M (1989) Identification of L-dopa-dopamine and L-dopa cell bodies in the rat mesencephalic dopaminergic cell systems. Synapse 4: 99–105PubMedGoogle Scholar
  34. Olanow CW (1992) An introduction to the free radical hypothesis in Parkinson's disease. Ann Neurol 32 [Suppl]: S2–9PubMedGoogle Scholar
  35. Perry TL, Yong VW, Ito M, Foulks JG, Wall RA, Godin DV, Clavier RM (1984) Nigrostriatal dopaminergic neurons remain undamaged in rats given high doses of L-DOPA and carbidopa chronically. J Neurochem 43: 990–993PubMedGoogle Scholar
  36. Piercey MF, Camacho-Ochoa M, Smith MW (1995) Functional roles for dopaminereceptor subtypes. Clin Neuropharmacol 18 [Suppl 1]: S34-S42Google Scholar
  37. Piercey MF, Hoffman WE, Smith MW, Hyslop DK (1996) Inhibition of dopamine neuron firing by pramipexole, a dopamine D3 receptor-preferring agonist: comparison to other agonists. Eur J Pharmacol 312: 35–44PubMedGoogle Scholar
  38. Prochiantz A, Daguet MC, Di Porzio U, Herbet A, Glowinski J (1983) In vitro studies on central dopaminergic neurons' development. Prog Brain Res 58: 365–368PubMedGoogle Scholar
  39. Robertson GS, Tham CS, Wilson C, Jakubovic A, Fibiger HC (1993) In vivo comparisons of the effects of quinpirole and the putative presynaptic dopaminergic agonists B-HT 920 and SND 919 on striatal dopamine and acetylcholine release. J Pharmacol Exp Ther 264: 1344–1351PubMedGoogle Scholar
  40. Sahakian BJ, Carlson KR, DeGirolami U, Bhawan J (1980) Functional and structural consequences of long-term dietary L-dopa treatment in mice. Commun Psychopharmacol 4: 169–176PubMedGoogle Scholar
  41. Salah RS, Kuhn DM, Galloway MP (1989) Dopamine autoreceptors modulate the phosphorylation of tyrosine hydroxylase in rat striatal slices. J Neurochem 52: 1517–1522PubMedGoogle Scholar
  42. Seroogy KB, Lundgren KH, Tran TM, Guthrie KM, Isackson PJ, Gall CM (1994) Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J Comp Neurol 342: 321–334PubMedGoogle Scholar
  43. Spina MB, Cohen G (1988) Exposure of striatal [corrected] synaptosomes to L-dopa increases levels of oxidized glutathione [published erratum appears in J Pharmacol Exp Ther (1989) 248(1): 478]. J Pharmacol Exp Ther 247: 502–507PubMedGoogle Scholar
  44. Steece-Collier K, Collier TJ, Sladek CD, Sladek JR (1990) Chronic levodopa impairs morphological development of grafted embryonic dopamine neurons. Exp Neurol 110: 201–208PubMedGoogle Scholar
  45. Stromberg I, Bjorklund L, Johansson M, Tomac A, Collins F, Oison L, Hoffer B, Kumpel C (1993) Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol 124: 401–412PubMedGoogle Scholar
  46. Tison F, Normand E, Jaber M, Aubert I, Bloch B (1991) Aromatic L-amino-acid decarboxylase (DOPA decarboxylase) gene expression in dopaminergic and serotoninergic cells of the rat brainstem. Neurosci Lett 127: 203–206PubMedGoogle Scholar
  47. Tomozawa Y, Appel SH (1986) Soluble striatal extracts enhance development of mesencephalic dopaminergic neurons in vitro. Brain Res 399: 111–124PubMedGoogle Scholar
  48. Youdim MB, Ben-Shachar D, Riederer P (1993) The possible role of iron in the etiopathology of Parkinson's disease [published erratum appears in Mov Disord (1993) 8(2): 255]. Mov Disord 8: 1–12PubMedGoogle Scholar
  49. Yu SJ, Lo ES, Cochran EJ, Lin DH, Faselis CJ, Klawans HL, Carvey PM (1994) Cerebrospinal fluid from patients with Parkinson's disease alters the survival of dopamine neurons in mesencephalic culture. Exp Neurol 126: 15–24PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • P. M. Carvey
    • 1
  • S. Pieri
    • 1
  • Z. D. Ling
    • 1
  1. 1.Neuropharmacology Research Laboratories, and Research Center for Brain Repair, Departments of Neurological Sciences and PharmacologyRush-Presbyterian-St. Luke's Medical CenterChicagoUSA

Personalised recommendations