Behavioural Assessment of the A2a/NR2B Combination in the Unilateral 6-OHDA-Lesioned Rat Model: A New Method to Examine the Therapeutic Potential of Non-Dopaminergic Drugs

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.

Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets

“…Drugs were administered orally in combination at clinically relevant doses to MPTP-treated marmosets without L-Dopa. This work confirms and extends previous studies in unilaterally-lesioned rats where the NR2B/A 2A antagonist combination proved to be significantly more effective than the individual drugs alone [ 15 , 16 ]. The most striking observation in the present primate study was the long-lasting restoration of movement which was not accompanied by any dyskinesia even though the primates had been L-Dopa primed prior to drug administration.…”

“…In previous experiments, performed with unilateral 6-ODHA-lesioned rats, the NR2B/A 2A combination significantly increased the level of locomotor activity. Instead of the typical contralateral rotations observed with dopaminergic drugs, the combination produced an increased exploratory activity accompanied by a restoration of fluid, coordinated and symmetrical quadripedal movements which looked similar to that observed with mildly stimulated non-lesioned rats [ 15 , 16 , 28 ]. In addition, we also noticed that after chronic treatment with the combination, the unilateral-lesioned rats did not develop any abnormal movements but rather developed an habituation to the testing environment resulting in decreased exploratory behaviour, making behavioural scoring difficult.…”

“…These rat data demonstrated that, when given in the absence of L-Dopa, an NR2B and an A 2A antagonist combination treatment was not only able to substantially restore the quantity of movement but could also significantly improve the quality of the movement when compared to L-Dopa. Furthermore, unlike L-Dopa, the combination treatment did not induce any involuntary movements in rats [ 16 ].…”

Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

“…To limit damage to noradrenergic neurons, imipramine (15 mg/kg, ip) was administered 15 min before 6-OHDA lesioning (Loiodice et al, 2018;Michel et al, 2015).…”

Targeting Adenosine Signaling in Parkinson's Disease: From Pharmacological to Non-pharmacological Approaches

“…In addition to the potential dual action on adenosinergic and dopaminergic systems, the complimentary action on glutamatergic and adenosinergic systems appeared as prospective targets for dual anti-parkinsonian approaches. The combination of A 2A AR antagonists and NR2B or mGlu 5 R antagonists has demonstrated attractive effects on motor activity with potential in the treatment of PD (Michel et al, 2014 , 2015 ; Beggiato et al, 2016 ). A 2A AR–CB 1 -D 2 DR-receptor-heteromer has been suggested as a component of motor alterations associated with dyskinesia and a possible target of multi-targeted drugs (Bonaventura et al, 2014 ; Pinna et al, 2014 ).…”