title: 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.
authors: UCB Biopharma SPRL, Neurosciences TA Biology, Braine l'Alleud, Belgium.
authors: Anne
authors: A
authors: Michel
authors: UCB Biopharma SPRL, Neurosciences TA Biology, Braine l'Alleud, Belgium.
authors: Patrick
authors: P
authors: Downey
authors: UCB Biopharma SPRL, Strategy & Alliance Management, Braine l'Alleud, Belgium.
authors: Xavier
authors: X
authors: Van Damme
authors: UCB Biopharma SPRL, Neurosciences TA Biology, Braine l'Alleud, Belgium.
authors: Catherine
authors: C
authors: De Wolf
authors: Philipps-University of Marburg, Behavioural Neuroscience, Marburg, Germany.
authors: Rainer
authors: R
authors: Schwarting
authors: UCB Biopharma SPRL, Neurosciences TA Biology, Braine l'Alleud, Belgium.
authors: Dieter
authors: D
authors: Scheller
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001545:Benserazide / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D004338:Drug Combinations; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D052160:Benzothiazoles; D015259:Dopamine Agents; D004338:Drug Combinations; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C005177:benserazide, levodopa drug combination; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; C000593256:tozadenant; D004298:Dopamine