The kinase Fyn mediates levodopa induced dyskinesias in Parkinson´s disease

BORDONE M; GOMEZ G; GERSHANIK OS; BORDONE M; GOMEZ G; GERSHANIK OS; FERRARIO JE; DAMIANICH A; TARAVINI I; FERRARIO JE; DAMIANICH A; TARAVINI I; SANZ BLASCO S; BERNARDI MA; AVALE E; SANZ BLASCO S; BERNARDI MA; AVALE E

Berlín

Congreso; 20th International Congress of Parkinson's Disease and Movement Disorders; 2016

International Parkinson and Movement Disorder Society

Objective: To pharmacologically manipulate the kinase Fyn as anovel 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 thedevelopment and maintenance of dyskinesia in PD and tested it as apotential pharmacological target to prevent LIDs. Very recent findingsfrom 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 assessmentof dopaminergic loss was determined at post-operatory recovery,observing spontaneous rotation, and cylinder test quantification. Well lesionedmice were randomly assigned to receive either vehicle or theFyn-inhibitor drug, Saracatinib (AZD0530) which was given before LDOPAor one week after, once dyskinesias were fully expressed. Wequantified AIMs every 3 days for one month. Postmortem, dopaminergicdenervation was carefully determined to ensure an equal level of degenerationin all groups.Results: We found, at the experimental doses tested here, that preadministrationof Saracatinib prevented the development of LID by 30%,while its co-administration, beginning one week after L-DOPA, andonce LID were fully expressed was not effective.Conclusions: Our data strongly suggest that Fyn is involved in thedevelopment of LID in a mouse model of PD, and we propose it as anovel pharmacological target to manage LID in PD patients. First, pharmacological data suggest that Fyn may be involved in the process ofLID induction, likely avoiding the consolidation of some maladaptiveprocess. However, once dyskinesias are established, the inhibition ofFyn seems to have no effect. Further work is still necessary to determinethe mechanisms by which Fyn is involved in the process and when itshould be targeted to control LIDs in PD.