Premium
Repurposing an established drug: an emerging role for methylene blue in L‐ DOPA ‐induced dyskinesia
Author(s) -
BariottodosSantos Keila,
PadovanNeto Fernando Eduardo,
Bortolanza Mariza,
dosSantosPereira Maurício,
RaismanVozari Rita,
Tumas Vitor,
Del Bel Elaine
Publication year - 2019
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.14079
Subject(s) - dyskinesia , soluble guanylyl cyclase , methylene blue , pharmacology , nitric oxide , chemistry , medicine , guanylate cyclase , parkinson's disease , biochemistry , catalysis , disease , photocatalysis
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.