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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Repurposing an established drug: an emerging role for methylene blue in L-DOPA-induced dyskinesia

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Autor(es):
Bariotto-dos-Santos, Keila [1, 2, 3] ; Padovan-Neto, Fernando Eduardo [1, 2, 3, 4] ; Bortolanza, Mariza [1, 2] ; dos-Santos-Pereira, Mauricio [1, 2, 5] ; Raisman-Vozari, Rita [6] ; Tumas, Vitor [1, 3] ; Del Bel, Elaine [1, 2, 5, 3]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ctr Interdisciplinary Res Appl Neurosci NAPNA, Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Sch Dent, Dept Morphol Physiol & Pathol, Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Sch Med, Dept Behav Neurosci, Ribeirao Preto, SP - Brazil
[4] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Psychol, Ribeirao Preto, SP - Brazil
[5] Univ Sao Paulo, Sch Med, Dept Physiol, Ribeirao Preto, SP - Brazil
[6] UPMC, Hop Salpetriere ICM, INSERM, Therapeut Expt Neurodegenerescence, Paris - France
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: European Journal of Neuroscience; v. 49, n. 6, SI, p. 869-882, MAR 2019.
Citações Web of Science: 2
Resumo

The nitric oxide (NO) system has been proven to be a valuable modulator of L-DOPA-induced dyskinesia in Parkinsonian rodents. NO activates the enzyme soluble guanylyl cyclase and elicits the synthesis of the second-messenger cGMP. Although we have previously described the anti-dyskinetic potential of NO synthase inhibitors on L-DOPA-induced dyskinesia, the effect of soluble guanylyl cyclase inhibitors remains to be evaluated. The aim of this study was to analyze whether the clinically available non-selective inhibitor methylene blue, or the selective soluble guanylyl cyclase inhibitor ODQ (1H-{[}1,2,4]oxadiazolo{[}4,3-a]quinoxalin-1-one), could mitigate L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Here, we demonstrated that methylene blue was able to reduce L-DOPA-induced dyskinesia incidence when chronically co-administered with L-DOPA during 3 weeks. Methylene blue chronic (but not acute) administration (2 weeks) was effective in attenuating L-DOPA-induced dyskinesia in rats rendered dyskinetic by a previous course of L-DOPA chronic treatment. Furthermore, discontinuous methylene blue treatment (e.g., co-administration of methylene blue and L-DOPA for 2 consecutive days followed by vehicle and L-DOPA co-administration for 5 days) was effective in attenuating dyskinesia. Finally, we demonstrated that microinjection of methylene blue or ODQ into the lateral ventricle effectively attenuated L-DOPA-induced dyskinesia. Taken together, these results demonstrate an important role of NO-soluble guanylyl cyclase-cGMP signaling on L-DOPA-induced dyskinesia. The clinical implications of this discovery are expected to advance the treatment options for patients with Parkinson's disease. (AU)

Processo FAPESP: 12/17626-7 - Mecanismos celulares e moleculares envolvidos no papel de neurotransmissores atípicos em transtornos neuropsiquiátricos
Beneficiário:Francisco Silveira Guimaraes
Linha de fomento: Auxílio à Pesquisa - Temático