Abstract
In Parkinson’s disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest “Tozadenant/Radiprodil” dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.
Highlights
Despite several decades of active research into novel therapeutic strategies for PD, L-Dopa given in combination with a peripheral dopa-decarboxylase inhibitor, still remains the most powerful drug to alleviate the motor symptoms of Parkinson’s disease [1, 2]
Using the Ethovision software, we reproduced the effect we had already observed with automated photobeam activity chambers: an increase in the distance traveled in 6-OHDA rats receiving the combination of A2A/NR2B antagonist drug in comparison to rats having received either drug alone
This effect was observed with the combination of Radiprodil 3 mg/kg and Tozadenant 30 mg/kg (RAD3/Tozadenant mg/kg (TOZ)) but not when lower doses of Radiprodil were combined with Tozadenant (Fig 1)
Summary
Despite several decades of active research into novel therapeutic strategies for PD, L-Dopa given in combination with a peripheral dopa-decarboxylase inhibitor, still remains the most powerful drug to alleviate the motor symptoms of Parkinson’s disease [1, 2]. Besides the post-synaptic adaptations associated to maladaptive striatal plasticity [4, 5], L-dopa-induced dyskinesia (LIDs) largely depend on: (1) the degree of dopamine neuron degeneration; (2) the type of treatment; and (3) the schedule of drug administration [6, 7]. Several strategies have been adopted to prevent or avoid the occurrence of L-Dopa-induced dyskinesia (LIDs). These include; delaying the use of dopaminergic treatment [1], modifying the route/dose to ensure continuous dopaminergic drug delivery [8], and the use of the non-selective N-methyl-D-aspartate (NMDA) receptor antagonist amantadine to counteract existing LIDs [9, 10]
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