Unprecedented Therapeutic Potential with a Combination of A2A/NR2B Receptor Antagonists as Observed in the 6-OHDA Lesioned Rat Model of Parkinson's Disease

Abstract

In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients.

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.…”

“…The doses used for the A 2A and NR2B antagonists combination were selected to provide the same plasma exposure values as those found to be active in the previously reported 6-OHDA rat study [ 15 ]. In the rodent PD model, the orally active dosing regimen of 3 mg/kg of Radiprodil combined with 30 mg/kg of Tozadenant was associated with plasma levels of 522 ng/mL Radiprodil and 6054 ng/mL Tozadenant (measured at 60 min).…”

“…NR2B antagonists, have been shown to have antiparkinsonian efficacy against motor symptoms in both rats [ 12 ] and primates when used in the absence of L-Dopa [ 13 ]. As there is evidence suggesting that the NMDA and A 2A receptors interact, at least within the striatum [ 14 ], the therapeutic potential of the combined administration of A 2A and NR2B antagonists was assessed in the unilateral 6-OHDA-lesioned rat PD model [ 15 ]. 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.…”

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

“…In a previous report, we demonstrated the enhanced potential of combining A 2A and NR2B receptor antagonists in a preclinical rat model of Parkinson’s disease [ 19 ]. The unilateral 6-hydroxydopamine (OHDA)-lesioned rat model mimics the status of advanced PD [ 20 ] and has been widely used for many years to assess the symptomatic effects of drugs.…”