Dataset Information

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.

SUBMITTER: Wang V

PROVIDER: S-EPMC8033754 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Wang Vicki V Kuo Tung-Tai TT Huang Eagle Yi-Kung EY Ma Kuo-Hsing KH Chou Yu-Ching YC Fu Zhao-Yang ZY Lai Li-Wen LW Jung Jin J Choi Hoi-Ii HI Choi Doo-Sup DS Li Yazhou Y Olson Lars L Greig Nigel H NH Hoffer Barry J BJ Chen Yuan-Hao YH

ACS pharmacology & translational science 20210316 2

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 ag ...[more]

PMID: 33860208

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Project description:The GLP-1 receptor agonist exendin-4 has recently shown good effects in a phase II clinical trial in Parkinson's disease (PD) patients. Here, a comparison of the new GLP-1/GIP dual receptor agonist DA5-CH and NLY01, a 40 kDa pegylated form of exendin-4, on motor impairments and reducing inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model is provided. The drug groups received either DA5-CH or NLY01 (25 nmol/kg) i.p. after daily MPTP intraperitoneal injection. Both drugs showed improvements in motor activity, open field experiments, rotarod tests, and gait analysis, but DA5-CH was more potent. Tyrosine hydroxylase expression in dopaminergic neurons was much reduced by MPTP and improved by DA5-CH, while NLY01 showed weak effects. When analyzing levels of α-synuclein (α-Syn), DA5-CH reduced levels effectively while NLY01 had no effect. When measuring the levels of the inflammation markers Toll-like receptor 4 (TLR4), specific markers of microglia activation (Iba-1), the marker of astrocyte activation glial fibrillary acidic protein (GFAP), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), and transforming growth factor β1 (TGF-β1), DA5-CH was very effective in reducing the chronic inflammation response, while NLY01 did not show significant effects. Levels of key growth factors such as Glial cell-derived neurotrophic factor (GDNF) and Brain-derived neurotrophic factor (BDNF) were much reduced by MPTP, and DA5-CH was able to normalize levels in the brain, while NLY01 showed little effect. The levels of pro-inflammatory cytokines (IL-6 and IL-Iβ) were much reduced by DA5-CH, too, while NLY01 showed no effect. In a separate experiment, we tested the ability of the two drugs to cross the blood-brain barrier. After injecting fluorescin-labelled peptides peripherally, the fluorescence in brain tissue was measured. It was found that the pegylated NLY01 peptide did not cross the BBB in meaningful quantities while exendin-4 and the dual agonist DA5-CH did. The results show that DA5-CH shows promise as a therapeutic drug for PD.

Project description:BackgroundNocturnal symptoms are common in Parkinson's disease (PD), which greatly affect the quality of life but are often overlooked in clinical settings. Treatment strategies that provide sustained dopaminergic stimulation may have sleep benefits.ObjectiveTo investigate the treatment effects of pramipexole (PPX) sustained release (SR) versus PPX immediate release (IR) on nocturnal symptoms in advanced PD patients with sleep disturbances.Materials and methodsIn this study, the PPX clinical trial (NCT00466167) was retrospectively analyzed for PD Sleep Scale (PDSS) total and domain scores in patients with advanced idiopathic PD receiving either PPX SR or PPX IR, who experienced motor fluctuations while on stable levodopa with a baseline PDSS total score of <90, indicating sleep disturbances. Analysis of covariance test was used to compare the adjusted mean changes at week 18 from baseline between treatment groups, after adjusting for pooled country and baseline scores.ResultsA total of 119 patients with PD reported sleep disturbances at baseline (PDSS <90; SR, n=59; IR, n=60). At week 18, patients receiving PPX SR reported numerically greater improvement of sleep disturbance than those receiving PPX IR, although the difference of 6.8 points was not statistically significant (adjusted mean changes in PDSS total score, SR=28.5 versus IR=21.7 points, P=0.165). Patients receiving PPX SR observed a numerically greater adjusted mean change in all PDSS domains compared with PPX IR. The overall proportions of patients with any adverse event were similar between both PPX SR and IR groups (62.7% versus 70.0%).ConclusionBoth the PPX formulations showed improvements in nocturnal symptoms in advanced PD patients with sleep disturbances and were generally well tolerated. Given the known pharmacokinetic profile of an SR formulation and numerical advantage in PDSS mean change over IR formulation, these preliminary evidences support future prospectively designed studies to investigate the effects of PPX SR for improved sleep.

Dataset Information

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

Publications

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

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