CONICET | Buscador de Institutos y Recursos Humanos

Objective: To pharmacologically manipulate the kinase Fyn as a novel target to control levodopa induced dyskinesias.Background: The management of levodopa induced dyskinesias (LID) in one of the greatest challenges in Parkinson?s disease (PD) research. Here we investigated the role of the tyrosine kinase Fyn in the development and maintenance of dyskinesia in PD and tested it as a potential pharmacological target to prevent LIDs. Very recent findings from our group (MDS meeting 2015) show that Fyn-KO mice are 30% less susceptible to develop LIDs.Methods: We induced LIDs in a mouse model of PD. A first assessment of dopaminergic loss was determined at post-operatory recovery, observing spontaneous rotation, and cylinder test quantification. Well-lesioned mice were randomly assigned to receive either vehicle or the Fyn-inhibitor drug, Saracatinib (AZD0530) which was given before L-DOPA or one week after, once dyskinesias were fully expressed. We quantified AIMs every 3 days for one month. Postmortem, dopaminergic denervation was carefully determined to ensure an equal level of degeneration in all groups.Results: We found, at the experimental doses tested here, that pre-administration of Saracatinib prevented the development of LID by 30%, while its co-administration, beginning one week after L-DOPA, and once LID were fully expressed was not effective.Conclusions: Our data strongly suggest that Fyn is involved in the development of LID in a mouse model of PD, and we propose it as a novel pharmacological target to manage LID in PD patients. First, pharmacological data suggest that Fyn may be involved in the process of LID induction, likely avoiding the consolidation of some maladaptive process. However, once dyskinesias are established, the inhibition of Fyn seems to have no effect. Further work is still necessary to determine the mechanisms by which Fyn is involved in the process and when it should be targeted to control LIDs in PD.