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Neurotherapeutics
Erschienen in:

01.04.2021 | Original Article

Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy

verfasst von: Lu-Lu Bu, Yi-Qi Liu, Yan Shen, Yun Fan, Wen-Bo Yu, Dong-Lang Jiang, Yi-Lin Tang, Yu-Jie Yang, Ping Wu, Chuan-Tao Zuo, James B. Koprich, Feng-Tao Liu, Jian-Jun Wu, Jian Wang

Erschienen in: Neurotherapeutics | Ausgabe 2/2021

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Abstract

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 μg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson’s disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson’s disease.
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Metadaten
Titel
Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy
verfasst von
Lu-Lu Bu
Yi-Qi Liu
Yan Shen
Yun Fan
Wen-Bo Yu
Dong-Lang Jiang
Yi-Lin Tang
Yu-Jie Yang
Ping Wu
Chuan-Tao Zuo
James B. Koprich
Feng-Tao Liu
Jian-Jun Wu
Jian Wang
Publikationsdatum
01.04.2021
Verlag
Springer International Publishing
Erschienen in
Neurotherapeutics / Ausgabe 2/2021
Print ISSN: 1933-7213
Elektronische ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-021-01018-5

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