A combined pharmacological strategy to block NMDA receptor function and reduce L-DOPA induced dyskinesias

SANZ BLASCO S; STARK, AMY; BORDONE M; FERRARIO JE; ISAJA, LUCIANA; GERSHANIK OS

San Diego

Congreso; Society for Neuroscience Congress 2018; 2018

International Society for Neurochemistry (ISN)

Levodopa (L-DOPA) induced dyskinesias (LID) are one of the most disabling side effects which appear after prolonged use of this drug for the treatment of Parkinson?s disease (PD). Finding a therapeutic alternative that could reduce LID is of great importance to improve the quality of life of PD patients. Moreover, gaining a more profound knowledge of the pathophysiology of LID is crucial for the development of more effective drugs and understanding the maladaptive changes taking place with the progression of the disease. Amantadine (or its analog, memantine) is a NMDA receptor (NMDA-R) antagonist which has been reported to reduce LID. However, its efficacy is limited and its safety and tolerability restricts its use in some patients. In this context, the aim of this work is to investigate pharmacological strategies, including novel target approaches, to reduce the use of amantadine. The inhibitor of the Src family kinases (SFKs) saracatinib (AZD0530), is an experimental drug currently under a phase 2a clinical trial for Alzheimer´s disease, for its blocking effect on Fyn, one of the members of the SFKs. Fyn mediates the regulation of the NMDA-R by phosphorylating Tyr-1472 at the NR2B subunit and regulates NMDA-R redistribution after dopamine depletion and L-DOPA treatment. Recently, we have shown that saracatinib partially reduces dyskinesias in a mouse model of LID (Sanz-Blasco et al., Mol Neurobiol 2017), suggesting a potential benefit of AZD0530 for PD patients under L-DOPA treatment.Here we have established an alternative approach targeting simultaneously the NMDA-R by two different strategies: reducing its availability at the membrane by inhibiting Fyn activity with saracatinib, and blocking the NMDA-R with amantadine. We have determined the intensity of LID on 6-OHDA lesioned mice treated with L-DOPA and challenged them either with saracatinib, amantadine or a combination of both drugs with the purpose of comparing their antidyskinetic properties at different concentrations. We have observed that, in dyskinetic mice with an equivalent severity of lesion, as determined by tyroxine hydroxilase immunohistochemistry, those treated with a combination of amantadine (at a lower dose than its effective concentration) and saracatinib (at a sub-therapeutic dose) showed reduced dyskinesia scores. LID reduction was greater when both drugs were administered in combination than when given individually at higher doses. Altogether, our results confirm the importance of the NMDA-R in the development of LID and point to a potential alternative strategy to control LID development in PD patients.