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Distinct Effects of Intranigral L-DOPA Infusion in the MPTP Rat Model of Parkinson’s Disease

  • Angela B. Reksidler
  • Marcelo M. S. LimaEmail author
  • Patrícia A. Dombrowski
  • Gabriela F. Barnabé
  • Monica L. Andersen
  • Sergio Tufik
  • Maria A. B. F. Vital
Chapter
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 73)

Abstract

The potential neuroprotective or neurotoxic effects of 3,4-dihydroxyphenylalanine (L-DOPA) are yet to be understood. We examined the behavioral, immunohistochemical, tyrosine hydroxylase (TH) expression and neurochemical parameters after an intranigral administration of L-DOPA (10 μM) in rats.. L-DOPA elicited a 30.5% reduction in dopaminergic neurons, while 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 μg μL−1) produced a 53.6% reduction. A combined infusion of MPTP and L-DOPA generated a 42% reduction of nigral neurons. Motor parameters revealed that both the MPTP and L-DOPA groups presented impairments; however, the concomitant administration evoked a partial restorative effect. In addition, MPTP and L-DOPA separately induced reductions of TH protein expression within the substantia nigra. In contrast, the coadministration of MPTP and L-DOPA did not demonstrate such difference. The striatal levels of dopamine were reduced after MPTP or L-DOPA, with an increased turnover only for the MPTP group. In view of such results, it seems reasonable to suggest that L-DOPA could potentially produce dopaminergic neurotoxicity.

Keywords

Animal model L-DOPA MPTP Neurotoxicity Parkinson’s disease Tyrosine hydroxylase 

Abbreviations

DA

Dopamine

L-DOPA

3,4-dihydroxyphenylalanine

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD

Parkinson’s disease

SN

Substantia nigra

SNpc

Substantia nigra pars compacta

TH-ir

Tyrosine hydroxylase immunoreactive

Notes

Acknowledgments

This work was supported by AFIP, FAPESP, and CAPES (PRODOC-Farmacologia UFSC to MMSL). The authors thank Mr. Adriano Zager and Mrs. Marilde Aires Costa for the technical assistance and Dr. Cláudio da Cunha for the HPLC analyses. MLA, ST, and MABFV are recipients of CNPq fellowships.

References

  1. Alexander T, Sortwell CE, Sladek CD et al (1997) Comparison of neurotoxicity following repeated administration of l-dopa, d-dopa, and dopamine to embryonic mesenphalic dopamine neurons in cultures derived from fisher 344 and Sprague-Dawley donors. Cell Transplantation 6:309–315CrossRefPubMedGoogle Scholar
  2. Basma RB, Morris EJ, Niklas WJ et al (1995) L-DOPA cytotoxicity to PC12 cells in culture is via its autooxidation. J Neurochem 64: 825–832CrossRefPubMedGoogle Scholar
  3. Benbir G, Ozekmekci S, Cinar M et al (2006) Features associated with the development of hallucinations in Parkinson's disease. Acta Neurol Scand 114:239–243CrossRefPubMedGoogle Scholar
  4. Bendir G, Özekmekçi S, Apaydin H et al (2006) A hospital-based study: risk factors in development of motor complications in 555 Parkinson’s patients on levodopa therapy. Clin Neurol Neurosurg 108:726–732CrossRefGoogle Scholar
  5. Braga R, Kouzmine I, Canteras NS et al (2005) Lesion of the substantia nigra pars compacta impairs delayed alternation in a Y-maze in rats. Exp Neurol 192:134–141CrossRefPubMedGoogle Scholar
  6. Broadhurst PL (1960) Experiments in psychogenetics. In: Eisenk HJ (ed) Experiments in personality. Routledge and Kegan Paul, LondonGoogle Scholar
  7. Da Cunha C, Gevaerd MS, Vital MABF et al (2001) Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson’s disease amnesia. Behav Brain Res 124:9–18CrossRefPubMedGoogle Scholar
  8. Da Cunha C, Angellucci MEM, Canteras NS et al (2002) The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson´s disease memory disabilities. Cell Mol Neurobiol 22:227–237CrossRefPubMedGoogle Scholar
  9. Fahn S, Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32:804–812CrossRefPubMedGoogle Scholar
  10. Ferro MM, Bellíssimo MI, Anselmo-Franci JA et al (2005) Comparison of bilaterally 6-OHDA- and MPTP-lesioned rats as models of early phase of Parkinson’s disease: Histological, neurochemical, motor and memory alterations. J Neurosci Methods 148:78–87CrossRefPubMedGoogle Scholar
  11. Fisher A, Biggs CS, Eradiri O et al (2000) Dual effects of L-3, 4- dihydroxyphenylalanine on aromatic L-amino acid decarboxilase, dopamine release on motor stimulation in the reserpine-treated rat: evidence that behavior is dopamine independent. Neuroscience 95:97–111CrossRefPubMedGoogle Scholar
  12. Golbe LI (1992) Young-onset Parkinson’s disease: a clinical review. Neurology 41:168–173Google Scholar
  13. Gross CE, Ravenscroft P, Dovero S et al (2003) Pattern of levodopa-induced striatal changes is different in normal and MPTP-lesioned mice. J Neurochem 84:1246–1255CrossRefPubMedGoogle Scholar
  14. Guigoni C, Dovero S, Aubert I et al (2005) Levodopa-induced dyskinesia in MPTP-treated macaques is not dependent on the extend and pattern of nigrostriatal lesioning. Eur J Neurosci 22:283–287CrossRefPubMedGoogle Scholar
  15. Konitsiotis S, Tsironis C (2006) Levodopa-induced dyskinesia and rotational behavior in hemiparkinsonian rats: independent features or components of the same phenomenon? Behav Brain Res 170:337–341CrossRefPubMedGoogle Scholar
  16. Kostrzewa RM, Nowak P, Kostrzewa JP et al (2005) Peculiarities of L-DOPA treatment of Parkinson's disease. Amino Acids 28:157–164CrossRefPubMedGoogle Scholar
  17. Lima MMS, Reksidler AB, Zanata SM et al (2006) Different parkinsonism models produce a time dependent induction of COX-2 in the substantia nigra of rats. Brain Res 1101:117–125CrossRefGoogle Scholar
  18. Lima MMS, Andersen ML, Reksidler AB et al (2007) The role of the substantia nigra pars compacta in regulating sleep patterns in rats. PLoS ONE 2:e513CrossRefPubMedGoogle Scholar
  19. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin protein reagent. J Bio Chem 193:265–275Google Scholar
  20. Lundblad M, Picconi B, Lindgreen H et al (2004) A model of L-dopa-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiol Dis 16:110–123CrossRefPubMedGoogle Scholar
  21. Maeda T, Cheng N-N, Kume T et al (1997) L-dopa neurotoxicity is mediated by glutamate release in cultured striatal neurons. Brain Res 771:159–162CrossRefPubMedGoogle Scholar
  22. Miyawaki E, Lyons K, Pahwa R et al (1997) Motor complications of chronic levodopa therapy in Parkinson’s disease. Clin Neuropharmacol 20:523–530CrossRefPubMedGoogle Scholar
  23. Miyoshi E, Wietzikoski S, Camplessei M et al (2002) Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions. Brain Res Bull 58:41–47CrossRefPubMedGoogle Scholar
  24. Muller T, Hefter H, Hueber R et al (2004) Is levodopa toxic? J Neurol 251:44–46CrossRefGoogle Scholar
  25. Myers CS, Halladay AK, Widmer DA et al (1999) Neurotoxic effects of amphetamine plus L-DOPA. Prog Neuro-Psychopharmacol Biol Psychiatry 23:731–740CrossRefGoogle Scholar
  26. Mytilineou C, Walker RH, Jnobaptiste R et al (2003) Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress. J Pharmacol Exp Ther 304:792–800CrossRefPubMedGoogle Scholar
  27. Olanow CW, Gauger BA, Cedarbaum MJ (1991) Temporal relantionships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson´s disease. Ann Neurol 29:556–569CrossRefPubMedGoogle Scholar
  28. Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic, San Diego, CAGoogle Scholar
  29. Perry JC, Hipólide DC, Tufik S et al (2005) Intra-nigral MPTP lesion in rats: behavioral and autoradiography studies. Exp Neurol 195:322–329CrossRefPubMedGoogle Scholar
  30. Quinn N, Critchley P, Marsden CD (1987) Young-onset Parkinson’s disease. Mov Disord 2:73–91CrossRefPubMedGoogle Scholar
  31. Rajput AH (2001) Levodopa prolongs life expectancy and is non-toxic to substantia nigra. Parkinsonism Relat Disord 8:95–100CrossRefPubMedGoogle Scholar
  32. Reksidler AB, Lima MMS, Zanata SM et al (2007) The COX-2 inhibitor parecoxib produces neuroprotective effects in MPTP-lesioned rats. Eur J Pharmacol 560(2):163–175CrossRefPubMedGoogle Scholar
  33. Reksidler AB, Lima MMS, Dombrowski P et al (2008) Repeated intranigral MPTP administration: a new protocol of prolonged locomotor impairment mimicking Parkinson's disease. J Neurosci Methods 167:268–277CrossRefPubMedGoogle Scholar
  34. Sarre S, Vandeneed D, Ebinger G et al (1998) Biotransformation of L-DOPA to dopamine in the substantia nigra of freely moving rats: effect of dopamine receptor agonists and antagonists. J Neurochem 70:1730–1739CrossRefPubMedGoogle Scholar
  35. Schrag A, Quinn N (2000) Dyskinesias and motor fluctuations in Parkinson’s disease: a community-based study. Brain 123: 2297–2305CrossRefPubMedGoogle Scholar
  36. Sundstrom E, Fredriksson A, Archer T (1990) Chronic neurochemical and behavioral changes in MPTP-lesioned C57BL/6 mice: a model for Parkinson´s disease. Brain Res 528:181–188CrossRefPubMedGoogle Scholar
  37. Tedroff JM (1997) The neuroregulatory properties of L-DOPA. A review of the evidence and potential role in the treatment of Parkinson´s disease. Rev Neurosci 8:195–204PubMedGoogle Scholar
  38. Thobois S, Delamarre-Damier F, Derkinderen P (2005) Treatment of motor dysfunctions in Parkinson’s disease: an overview. Clin Neurol Neurosurg 107:269–281CrossRefPubMedGoogle Scholar
  39. von Bohlen und Halbach O (2005) Animal models of Parkinson´s disease. Neurodegener Dis 2:313–320CrossRefGoogle Scholar
  40. Wang H, Pickel VM (2002) Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus. J Comp Neurol 442:392–404CrossRefPubMedGoogle Scholar
  41. Ziv I, Zilkha-Falb R, Offen D et al (1997) Levodopa induces apoptosis in cultured neuronal cells-a possible accelerator of nigrostriatal degeneration in Parkinson´s disease? Mov Disord 12:17–23CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien Printed in Germany 2009

Authors and Affiliations

  • Angela B. Reksidler
    • 1
  • Marcelo M. S. Lima
    • 2
    Email author
  • Patrícia A. Dombrowski
    • 1
  • Gabriela F. Barnabé
    • 4
  • Monica L. Andersen
    • 3
  • Sergio Tufik
    • 3
  • Maria A. B. F. Vital
    • 1
  1. 1.Departamento de FarmacologiaUniversidade Federal do ParanáCuritibaBrasil
  2. 2.Departamento de FarmacologiaUniversidade Federal de Santa CatarinaSanta CatarinaBrasil
  3. 3.Departamento de PsicobiologiaUniversidade Federal de São PauloSão PauloBrasil
  4. 4.Departamento de NeurofisiologiaUniversidade Federal de São PauloSão PauloBrasil

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