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

• Published in: PloS one 2017-08, Vol.12 (8), p.e0182887-e0182887
• Main Authors: Michel, Anne, Nicolas, Jean-Marie, Rose, Sarah, Jackson, Michael, Colman, Peter, Briône, Willy, Sciberras, David, Muglia, Pierandrea, Scheller, Dieter K, Citron, Martin, Downey, Patrick
• Format: Article
• Language: English
• Subjects: Adenosine; Animals; Antiparkinson agents; Antiparkinson Agents - pharmacology; Benzothiazoles - pharmacology; Biology and Life Sciences; Callithrix; Care and treatment; Cocaine; Complications; Dihydroxyphenylalanine; Dopa; Dopamine; Dopamine receptors; Dosage and administration; Drug Administration Schedule; Drug Combinations; Drug development; Drug dosages; Drug Evaluation, Preclinical; Drug Synergism; Drugs; Dyskinesia; Dyskinesia, Drug-Induced - prevention & control; Female; Gene Expression; Kinases; Levodopa; Male; Marmosets; Medicine and Health Sciences; Monkeys & apes; Motor activity; Motor Activity - drug effects; Motor Activity - physiology; Motor task performance; Movement disorders; MPTP; MPTP Poisoning - drug therapy; MPTP Poisoning - genetics; MPTP Poisoning - metabolism; MPTP Poisoning - physiopathology; Neurodegenerative diseases; Pain; Parkinson disease; Parkinson's disease; Parkinsons disease; Pharmaceutical sciences; Phosphorylation; Primates; Rats; Receptors, Adenosine A2 - genetics; Receptors, Adenosine A2 - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Research and Analysis Methods; Restoration; Rodents; Treatment Outcome
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182887

Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD. When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects. We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic.