PT320, Sustained-Release Exendin-4, Mitigates L-DOPA-Induced Dyskinesia in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease

Frontiers in Neuroscience

Yun Wang¹  Yung-Yung Yang¹  Seong-Jin Yu¹  Shuchun Chen¹  Elliot J. Glotfelty²  Barry J. Hoffer³  Doo-Sup Choi⁴  Nigel H. Greig⁵  Jin Jung⁶  Hee Kyung Kim⁶  Ho-Il Choi⁶ 

[1] Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan;Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden;Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, United States;Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, United States;Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States;Peptron Inc., Daejeon, South Korea;

关键词: Parkinson’s disease;    levodopa;    L-DOPA-induced dyskinesia;    glucagon-like peptide-1;    exendin-4;    PT320;   

DOI  :  10.3389/fnins.2020.00785

来源: DOAJ

【 摘 要 】

BackgroundWe previously demonstrated that subcutaneous administration of PT320, a sustained-release (SR) form of exendin-4, resulted in the long-term maintenance of steady-state exenatide (exendin-4) plasma and target levels in 6-hydroxydopamine (6-OHDA)-pretreated animals. Additionally, pre- or post-treatment with PT320 mitigated the early stage of 6-OHDA-induced dopaminergic neurodegeneration. The purpose of this study was to evaluate the effect of PT320 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the rat 6-OHDA model of Parkinson’s disease.MethodsAdult male Sprague–Dawley rats were unilaterally lesioned in the right medial forebrain bundle by 6-OHDA. L-DOPA and benserazide were given daily for 22 days, starting from 4 weeks after lesioning. PT320 was co-administered weekly for 3 weeks. AIM was evaluated on days 1, 16, and 22 after initiating L-DOPA/benserazide + PT320 treatment. Brain tissues were subsequently collected for HPLC measurements of dopamine (DA) and metabolite concentrations.ResultsL-DOPA/benserazide increased AIMs of limbs and axial as well as the sum of all dyskinesia scores (ALO) over 3 weeks. PT320 significantly reduced the AIM scores of limbs, orolingual, and ALO. Although PT320 did not alter DA levels in the lesioned striatum, PT320 significantly attenuated 6-OHDA-enhanced DA turnover.ConclusionPT320 attenuates L-DOPA/benserazide-induced dyskinesia in a 6-OHDA rat model of PD and warrants clinical evaluation to mitigate Parkinson’s disease in humans.

【 授权许可】

Unknown