The fyn inhibitor saracatinib reduces levodopa induced dyskinesia in parkinson?s disease.

SARA SANZ BLASCO; ANA DAMIANICH; OSCAR GERSHANIK; MARÍA ALEJANDRA BERNARDI; MELINA BORDONE; MARÍA ELENA AVALE; GIMENA GOMEZ; IRENE TARAVINI; JUAN ESTEBAN FERRARIO

Mar del Plata

Congreso; XLVIII Annual meeting of the Argentinian Society of Experimental Pharmacology.; 2016

Sociedad Argentina de Farmacología Experimental

Levodopa-induced dyskinesia (LID) is one of the major side effects of the treatment of Parkinson´s disease (PD), a neurodegenerative condition caused by progressive degeneration of dopaminergic neurons in the SubstantiaNigra pars compacta. The aim of this study was to pharmacologically manipulate thetyrosine kinase Fyn as a novel target to control LID. We investigated the role of Fyn in the development and maintenance of dyskinesia in PD and tested it as a potential pharmacological target to prevent LID. To reach this goal we induced LID in a mouse model of PD by dopaminergic denervation induced by 6-OHDA. We evaluated the degree of dopaminergic loss by observation of the spontaneous rotation, and cylinder test quantification. Mice that were correctly denervated were randomly assigned to receive either vehicle or the Fyn-inhibitor Saracatinib (AZD0530), which was given starting 8 days before L-DOPA or 7 days after LID has been started. In both cases, Saracatinib and L-DOPA treatment Were continued until the end of the protocol, which last for 25 days on which LIDwere quantified every 3 days. Finally, dopaminergic denervation was carefully determined postmortem, to ensure the same level of degeneration in all groups. At the experimental doses used in this procedure, we found that pre-administration of Saracatinib prevented by 30% the development of LID. But in the case that co-administration began one week after L-DOPA, when LID were fully developed, the treatment was not effective. This data strongly supports the idea that Fyn is involved in the development of LID in our model of PD, maybe avoiding the consolidation of some maladaptive process. However, when LID are already established, the inhibition of Fyn seems to have no effect. We propose to block Fyn as a novel pharmacological target to manage LID in PD patients, although further work is still necessary to improve Fyn inhibition, either by development of new drugs or by improving Saracatinib delivery.