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Counteraction by Nitric Oxide Synthase Inhibitor of Neurochemical Alterations of Dopaminergic System in 6-OHDA-Lesioned Rats Under l-DOPA Treatment

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Abstract

Nitric oxide synthase inhibitors reduce l-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371–392, 2005) 4-dihydroxyphenylalanine (l-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3 weeks, rats were treated during 21 days with l-DOPA/benserazide (30 mg/kg/7.5 mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before l-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. l-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. l-DOPA-induced dyskinesia was mitigated by 7-nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non-lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of l-DOPA-induced dyskinesia with potential utilization of nitric oxide synthase inhibitors for treatment.

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Abbreviations

7-NI:

7-Nitroindazole

6-OHDA:

6-Hydroxydopamine

AIMs:

Abnormal involuntary movements

cGMP:

Cyclic guanosine monophosphate

DAT:

Dopamine transporter

DOPAC:

3,4-Dihydroxyphenylacetic acid

GABA:

Gamma-aminobutyric acid

l-NAME:

N G-nitro-l-arginine methyl ester

nNOS:

Neuronal nitric oxide synthase

NOS:

Nitric oxide synthase

NMDA:

N-Methyl-d-aspartate acid

NADPH:

Nicotinamide adenine dinucleotide phosphate

SN:

Substantia nigra

VTA:

Ventral tegmental area

TH:

Tyrosine hydroxylase

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Acknowledgments

The authors are most obliged to Danielle de Oliveira Tavares and Aline Luciana Tolentino for the excellent photomicrography and help with histological analyses. We also acknowledge grants from FAPESP-Projeto Temático 2012, FAPESP-INSERM, CAPES-COFECUB, CNPQ, and CNPQ-Science without Border project. FAPESP supported Fernando E. Padovan-Neto with a PhD fellowship. Aline Luciana Tolentino and Angélica C. Romano-Dutra were CNPQ-PIBIC fellowship holders. E.A.Del-Bel is a Senior Research from CNPq.

Conflict of interest

We declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author information

Authors and Affiliations

  1. Department of Morphology, Physiology and Pathology, School of Odontology, University of São Paulo, Campus Ribeirão Preto, Av. Café S/N, Ribeirão Preto, SP, 14040-904, Brazil

    Elaine Del-Bel, Fernando Eduardo Padovan-Neto, Célia Aparecida da-Silva, Janete Anselmo-Franci & Angélica Caroline Romano-Dutra

  2. Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil

    Elaine Del-Bel, Fernando Eduardo Padovan-Neto, Célia Aparecida da-Silva & Francisco Silveira Guimaraes

  3. Department of Pharmacology, Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil

    Francisco Silveira Guimaraes

  4. Department of Behavioral Neurosciences, Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, SP, 14049-900, Brazil

    Elaine Del-Bel & Fernando Eduardo Padovan-Neto

  5. Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG, 31270-910, Brazil

    Raphael Escorsim Szawka

  6. INSERM UMR-S 975, UPMC, CRICM, Experimental Therapeutics of Neurodegeneration, 75013, Paris, France

    Rita Raisman-Vozari

  7. Faculté de Médecine, Université Pierre & Marie Curie-Paris 6, CNRS, UMR 7225, 75013, Paris, France

    Rita Raisman-Vozari

Authors
  1. Elaine Del-Bel
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  2. Fernando Eduardo Padovan-Neto
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  3. Raphael Escorsim Szawka
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  4. Célia Aparecida da-Silva
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  5. Rita Raisman-Vozari
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  6. Janete Anselmo-Franci
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  7. Angélica Caroline Romano-Dutra
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  8. Francisco Silveira Guimaraes
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Corresponding author

Correspondence to Elaine Del-Bel.

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Del-Bel, E., Padovan-Neto, F.E., Szawka, R.E. et al. Counteraction by Nitric Oxide Synthase Inhibitor of Neurochemical Alterations of Dopaminergic System in 6-OHDA-Lesioned Rats Under l-DOPA Treatment. Neurotox Res 25, 33–44 (2014). https://doi.org/10.1007/s12640-013-9406-3

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  • DOI: https://doi.org/10.1007/s12640-013-9406-3

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