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

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Birth, Life and Death of Dopaminergic Neurons in the Substantia Nigra

Part of the book series: Journal of Neural Transmission. Supplementa ((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.

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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

References

  • 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 6:309–315

    Article  CAS  PubMed  Google Scholar 

  • Basma RB, Morris EJ, Niklas WJ et al (1995) L-DOPA cytotoxicity to PC12 cells in culture is via its autooxidation. J Neurochem 64: 825–832

    Article  CAS  PubMed  Google Scholar 

  • Benbir G, Ozekmekci S, Cinar M et al (2006) Features associated with the development of hallucinations in Parkinson's disease. Acta Neurol Scand 114:239–243

    Article  CAS  PubMed  Google Scholar 

  • 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 108:726–732

    Article  Google Scholar 

  • 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 192:134–141

    Article  CAS  PubMed  Google Scholar 

  • Broadhurst PL (1960) Experiments in psychogenetics. In: Eisenk HJ (ed) Experiments in personality. Routledge and Kegan Paul, London

    Google Scholar 

  • 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 124:9–18

    Article  PubMed  Google Scholar 

  • 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 22:227–237

    Article  PubMed  Google Scholar 

  • Fahn S, Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32:804–812

    Article  CAS  PubMed  Google Scholar 

  • 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 148:78–87

    Article  CAS  PubMed  Google Scholar 

  • 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 95:97–111

    Article  CAS  PubMed  Google Scholar 

  • Golbe LI (1992) Young-onset Parkinson’s disease: a clinical review. Neurology 41:168–173

    Google Scholar 

  • 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 84:1246–1255

    Article  CAS  PubMed  Google Scholar 

  • 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 22:283–287

    Article  PubMed  Google Scholar 

  • 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 170:337–341

    Article  CAS  PubMed  Google Scholar 

  • Kostrzewa RM, Nowak P, Kostrzewa JP et al (2005) Peculiarities of L-DOPA treatment of Parkinson's disease. Amino Acids 28:157–164

    Article  CAS  PubMed  Google Scholar 

  • 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 1101:117–125

    Article  CAS  Google Scholar 

  • 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:e513

    Article  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin protein reagent. J Bio Chem 193:265–275

    CAS  Google Scholar 

  • 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 16:110–123

    Article  CAS  PubMed  Google Scholar 

  • Maeda T, Cheng N-N, Kume T et al (1997) L-dopa neurotoxicity is mediated by glutamate release in cultured striatal neurons. Brain Res 771:159–162

    Article  CAS  PubMed  Google Scholar 

  • Miyawaki E, Lyons K, Pahwa R et al (1997) Motor complications of chronic levodopa therapy in Parkinson’s disease. Clin Neuropharmacol 20:523–530

    Article  CAS  PubMed  Google Scholar 

  • 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 58:41–47

    Article  CAS  PubMed  Google Scholar 

  • Muller T, Hefter H, Hueber R et al (2004) Is levodopa toxic? J Neurol 251:44–46

    Article  Google Scholar 

  • Myers CS, Halladay AK, Widmer DA et al (1999) Neurotoxic effects of amphetamine plus L-DOPA. Prog Neuro-Psychopharmacol Biol Psychiatry 23:731–740

    Article  CAS  Google Scholar 

  • 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 304:792–800

    Article  CAS  PubMed  Google Scholar 

  • 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 29:556–569

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Academic, San Diego, CA

    Google Scholar 

  • Perry JC, Hipólide DC, Tufik S et al (2005) Intra-nigral MPTP lesion in rats: behavioral and autoradiography studies. Exp Neurol 195:322–329

    Article  PubMed  Google Scholar 

  • Quinn N, Critchley P, Marsden CD (1987) Young-onset Parkinson’s disease. Mov Disord 2:73–91

    Article  CAS  PubMed  Google Scholar 

  • Rajput AH (2001) Levodopa prolongs life expectancy and is non-toxic to substantia nigra. Parkinsonism Relat Disord 8:95–100

    Article  CAS  PubMed  Google Scholar 

  • 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):163–175

    Article  CAS  PubMed  Google Scholar 

  • 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 167:268–277

    Article  CAS  PubMed  Google Scholar 

  • 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 70:1730–1739

    Article  CAS  PubMed  Google Scholar 

  • Schrag A, Quinn N (2000) Dyskinesias and motor fluctuations in Parkinson’s disease: a community-based study. Brain 123: 2297–2305

    Article  PubMed  Google Scholar 

  • 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 528:181–188

    Article  CAS  PubMed  Google Scholar 

  • 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 8:195–204

    CAS  PubMed  Google Scholar 

  • Thobois S, Delamarre-Damier F, Derkinderen P (2005) Treatment of motor dysfunctions in Parkinson’s disease: an overview. Clin Neurol Neurosurg 107:269–281

    Article  PubMed  Google Scholar 

  • von Bohlen und Halbach O (2005) Animal models of Parkinson´s disease. Neurodegener Dis 2:313–320

    Article  Google Scholar 

  • 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 442:392–404

    Article  CAS  PubMed  Google Scholar 

  • 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 12:17–23

    Article  CAS  PubMed  Google Scholar 

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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.

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Authors and Affiliations

  1. Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, PR, Brasil

    Angela B. Reksidler, Patrícia A. Dombrowski & Maria A. B. F. Vital

  2. Departamento de Farmacologia, Universidade Federal de Santa Catarina, Santa Catarina, SC, Brasil

    Marcelo M. S. Lima

  3. Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

    Monica L. Andersen & Sergio Tufik

  4. Departamento de Neurofisiologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

    Gabriela F. Barnabé

Authors
  1. Angela B. Reksidler
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  2. Marcelo M. S. Lima
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  3. Patrícia A. Dombrowski
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  4. Gabriela F. Barnabé
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  5. Monica L. Andersen
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  6. Sergio Tufik
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  7. Maria A. B. F. Vital
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Correspondence to Marcelo M. S. Lima .

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Editors and Affiliations

  1. Fac. Medicina e Chirurgia, Università di Palermo, Corso Tukory 129, Palermo, 90134, Italy

    Giuseppe Giovanni

  2. Mario Negri, Istituto di Ricerche Farmacologiche, Via Nazionale 8, Santa Maria Imbaro, 66030, Italy

    Vincenzo Di Matteo

  3. Mario Negri, Istituto di Ricerche Farmacologiche, Via Nazionale 8, Santa Maria Imbaro, 66030, Italy

    Ennio Esposito

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Reksidler, A.B. et al. (2009). Distinct Effects of Intranigral L-DOPA Infusion in the MPTP Rat Model of Parkinson’s Disease. In: Giovanni, G., Di Matteo, V., Esposito, E. (eds) Birth, Life and Death of Dopaminergic Neurons in the Substantia Nigra. Journal of Neural Transmission. Supplementa, vol 73. Springer, Vienna. https://doi.org/10.1007/978-3-211-92660-4_21

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  • DOI: https://doi.org/10.1007/978-3-211-92660-4_21

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