Objective: Investigate the potential of tozadenant (TOZ) to alleviate the non-motor symptoms of Parkinson’s disease using multiple animal models.

Background: TOZ is an oral, selective adenosine A2a receptor antagonist that is being developed for the treatment of Parkinson’s disease (PD). TOZ improves motor function in animal models of PD (Michel et al, 2015), has shown promise in early clinical investigations as a treatment of motor symptoms of PD (Hauser et al, 2014), and is currently in phase 3 clinical testing for the treatment of PD as an adjunct to L-dopa therapy. The biology of the A2a receptor and the mechanism of action of TOZ raises the possibility that it could also modulate the non-motor symptoms of PD. Thus, TOZ was investigated in animal models of depression and anxiety.

Methods: TOZ was tested for its effect as a monotherapy in two animal models of depression, the rat forced swim test and the rat chronic mild stress-induced anhedonia test, and one model of anxiety, the rat elevated plus-maze.

Results: In the forced swim model, single oral doses of TOZ dose-dependently reduced time spent immobile, with a low dose of 3 mg/kg showing a slight (10.6%, p=0.13) reduction, and higher doses of 10 and 30 mg/kg showing significant reductions (27.3%, p=0.02, and 31.5%, p=0.003, respectively) in immobility time versus vehicle control. In the chronic stress-induced anhedonia model, once-daily IP doses of 1 or 3 mg/kg TOZ significantly reduced the anhedonia index in stressed animals compared to vehicle controls; the anhedonia index in TOZ-treated animals returned to pre-stress baseline level, suggesting a reversal of the stress-induced depression-like state. In the elevated plus-maze test, single oral doses of TOZ showed dose dependent anxiolytic effects, with the highest dose tested of 30 mg/kg showing significant effects on all response factors measured (e.g. 152% increase in time in open arms , p=0.02).

Conclusions: The doses used in these animal models result in drug exposures similar to those achieved in clinical studies on TOZ.   The antidepressant and anxiolytic-like effects demonstrated in these animal models support further investigation of TOZ for the treatment of non-motor symptoms of PD in clinical trials.

References: Michel A, Downey P, Van Damme X, De Wolf C, Schwarting R, Scheller D.  PLoS One. 2015 Aug 31;10(8):e0135949.

Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, Kozyolkin O, Neale A, Resburg C, Meya U, Kenney C, Bandak S.  Lancet Neurol. 2014 Aug;13(8):767-76.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-of-tozadenant-in-animal-models-of-non-motor-symptoms-of-parkinsons-disease/