期刊
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
卷 4, 期 2, 页码 858-869出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.1c00013
关键词
Parkinson's disease; MitoPark mice; exenatide; PT320; GLP-1; exendin-4
资金
- Ministry of Science and Technology of Taiwan, ROC [MOST-2314-B-016-001-MY3, MOST-108-2314-B-016-027]
- Tri-Service General Hospital of Taiwan [TSGHC108-098, TSGH-C108-094, TSGH-D109-100, TSGH-D109-097]
- National Defense Medical Center, ROC [MAB-108-025, MND-MAB-110-077]
- Technological Innovation R&D Program (Republic of Korea) [S2174574]
- Bio and Medical Technology Development Program of the National Research Foundation, Republic of Korea [NRF-2014M3A9B5073868]
- Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA
- USPHS, NIH [NS0194152-S1]
- Swedish Research Council [K2012-62X-03185-42-4]
- Swedish Brain Foundation
- Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic
- US PHS, NIH [AA018779]
- Korea Evaluation Institute of Industrial Technology (KEIT) [S2174574] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2014M3A9B5073868] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
GLP-1 agonists, such as PT320, show potential in improving behavioral and cellular parameters in a mouse model of Parkinson's disease (PD), particularly in the early stages of the disease. The efficacy may be closely related to enhanced dopamine midbrain function.
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.
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