Sustained release GLP-1 agonist PT320 delays disease progression in a mouse model of Parkinson's disease

Vicki Wang, Tung Tai Kuo, Eagle Yi Kung Huang, Kuo Hsing Ma, Yu Ching Chou, Zhao Yang Fu, Li Wen Lai, Jin Jung, Hoi Ii Choi, Doo Sup Choi, Yazhou Li, Lars Olson, Nigel H. Greig, Barry J. Hoffer, Yuan Hao Chen

Research output: Contribution to journalArticlepeer-review

Abstract

GLP-1 agonists have become increasingly interesting as a new Parkinson's disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. "Motivated"behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.

Original languageEnglish (US)
JournalACS Pharmacology and Translational Science
DOIs
StateAccepted/In press - 2021

Keywords

  • Exenatide
  • Exendin-4
  • GLP-1
  • MitoPark mice
  • Parkinson's disease
  • PT320

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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