di Paolo, Therese, Gregoire, Laurent, Feuerbach, Dominik, Elbast, Walid, Weiss, Markus and Gomez-Mancilla, Baltazar (2014) AQW051, a novel, and selective nicotinic acetylcholine receptor α7 partial agonist, reduces L-Dopa-induced dyskinesias and extends the duration of L-Dopa effects in parkinsonian monkeys. Parkinsonism Relat Disord.

Abstract

Nicotinic acetylcholine receptor (nAChR)-mediated signaling pathways have been implicated in levodopa (L-Dopa)-induced dyskinesias (LID). Recent studies have used β2 subtype selective nAChR agonists to target the cholinergic system and alleviate LID in L-Dopa-treated monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion. This study investigated the novel selective α7 nAChR partial agonist AQW051 for its antidyskinetic activity in L-Dopa-treated MPTP-lesioned monkeys. Six Macaca fascicularis MPTP monkeys were treated to develop reproducible dyskinesias by repeated administration of L-Dopa. AQW051 (2, 8, and 15 mg/kg) administered 1 h before L-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the anti-parkinsonian response to L-Dopa, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced following treatment with 15 mg/kg for the total, 1 h, and peak periods achieving a median reduction of 60% across the total study period. In order to explore the exposure-effect relationship, plasma concentration-time data were collected from three satellite animals treated with 15 mg/ml AQW051. No abnormal behavioral or physiological effects were reported. Our results show that by combining AQW051 at a high dose with L-Dopa, dyskinesias can be reduced without compromising the benefits of L-Dopa and can extend the duration of the L-Dopa anti-parkinsonian response in MPTP monkeys. This supports the therapeutic use of nAChR α7 agonists to modulate LID and the potential to extend the therapeutic window for L-Dopa.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/20884