PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

Abstract

To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.