Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson's disease

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...

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Published in:	PloS one 2014-12, Vol.9 (12), p.e114086
Main Authors:	Michel, Anne, Downey, Patrick, Nicolas, Jean-Marie, Scheller, Dieter
Format:	Article
Language:	eng
Subjects:	Adenosine Adenosine A2 Receptor Antagonists - pharmacology Adenosine A2 Receptor Antagonists - therapeutic use Analysis of Variance Animals Benzothiazoles - pharmacology Biology Biology and Life Sciences Brain Complications Dihydroxyphenylalanine Dopamine Dopamine receptors Drug development Drug interaction Drug Therapy, Combination - methods Drugs Kinases Levodopa Levodopa - therapeutic use Mass Spectrometry Medical screening Medicine and Health Sciences Motor activity Motor Activity - drug effects Movement disorders Neurodegenerative diseases Neurosciences Oxidopamine - adverse effects Oxidopamine - metabolism Parkinson Disease, Secondary - chemically induced Parkinson Disease, Secondary - drug therapy Parkinson's disease Parkinsons disease Pharmacology Piperidines - pharmacology Purines - pharmacology Pyrimidines - pharmacology Rats Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Research and Analysis Methods Rodents Studies Therapy Triazoles - pharmacology Variance analysis
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Summary:	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.
ISSN:	1932-6203 1932-6203