Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson’s Disease

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.

Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling

“…Liratuglide-treated groups also showed significantly increased concentrations of neurotransmitters including dopamine in hippocampal tissue. Similar beneficial results were obtained with exenatide, a GLP-1R agonist, showing enhanced dopamine midbrain function and behavioral improvement [ 75 ]. Several butyrogenic microbial species can naturally enhance GLP-1 levels and brain GLP-1R expression to positively affect dopamine concentration and improve neurobehavioral deficits.…”

Attenuated Postprandial GLP-1 Response in Parkinson’s Disease

“…Disrupted secretion of GLP-1 in PD patients may be clinically important, and careful elucidation of causative mechanisms could offer new therapeutic strategies. GLP-1 is known to have neuroprotective properties that are disease-modifying in models of PD (Bertilsson et al, 2008;Kim et al, 2009;Li et al, 2009Li et al, , 2020Yun et al, 2018;Fang et al, 2020;Salles et al, 2020;Zhang et al, 2020;Wang et al, 2021). Activation of microglia and the resulting neuroinflammation have been heavily implicated in PD.…”

“…There is interest in the potential neuroprotective role of the incretin hormone glucagonlike peptide 1 (GLP-1) in PD based on compelling evidence in vitro, in rodent models, and in humans (Athauda and Foltynie, 2016;Kim et al, 2017;Bayram and Litvan, 2020;Glotfelty et al, 2020;Li et al, 2020;Salles et al, 2020;Zhang et al, 2020;Wang et al, 2021). The GLP-1 receptor agonist Exendin-4 prevents 6-hydroxydopamine (6-OHDA)induced death of dopaminergic neurons in neuronal culture (Li et al, 2009;Athauda and Foltynie, 2016), and intraventricular administration protects mice from MPTP-induced dopaminergic cell loss and improves motor function in animal models of PD (Li et al, 2009).…”

“…The GLP-1 receptor agonist Exendin-4 prevents 6-hydroxydopamine (6-OHDA)induced death of dopaminergic neurons in neuronal culture (Li et al, 2009;Athauda and Foltynie, 2016), and intraventricular administration protects mice from MPTP-induced dopaminergic cell loss and improves motor function in animal models of PD (Li et al, 2009). Follow-up studies demonstrate that systemic administration of Exendin-4 preserves motor function, decreases microglial activation, and inhibits inflammatory cytokine expression induced by MPTP in mice (Kim et al, 2009), rescues nigrostriatal dopaminergic neurons from the effects of 6-OHDA in rats (Bertilsson et al, 2008), and a sustained release formula (PT320) delays progression of PD-like symptoms in a genetic mouse model of PD (Wang et al, 2021). Other GLP-1 receptor-targeting compounds are also effective at modulating PD-like outcomes in rodents.…”

The Role of Microglia in the Development of Neurodegenerative Diseases

“…In that study, the GLP-1R agonist NLY01 effectively suppressed the α-synuclein preformed fibril (α-Syn PFF)-induced microglial activation marker Iba-1 and the secretion of TNF-α, IL-1α, and C1q, and exerted inhibitory effects on the nuclear translocation of NF-κB in α-Syn PFF-stimulated microglia [117]. A recent observation from Wang et al showed that the GLP-1R agonist PT320 ameliorated the progression of PD through improvements in behavior and DA midbrain function in a progressive PD mouse model [150]. Therefore, these results suggest that the activation of GLP-1R in microglia could suppress A1 neurotoxic astrocytes and ameliorate progression in PD (Figure 2).…”