AUTHOR=Liu Wen-Hong , Liu Cui , Xue Yan , Sun Xiang-Rong , Chen Xin-Yi , Chen Lei 

TITLE=Activation of GLP-1R modulates the spontaneous discharge of nigral dopaminergic neurons and motor behavior in mice with chronic MPTP Parkinson's disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 17 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1529919

DOI=10.3389/fnagi.2025.1529919

ISSN=1663-4365

ABSTRACT=The gradual decline of nigral dopaminergic neurons is the main cause of Parkinson's disease (PD), yet as of now, there exists no conclusive therapeutic intervention. Glucagon-like peptide-1 (GLP-1) is an incretin, which is also a key substance regulating neuronal activity and synaptic transmission. GLP-1 receptors (GLP-1Rs) are widely expressed in the central nervous system. Chronic administration of low doses of 1-methyl-4-phenyl, 1,2,3,6-tetrahydropiridine (MPTP) mitigates mortality in mice during the modeling phase, thereby more closely mirroring the progression of PD. This study aims to observe the effects of GLP-1 receptor agonists (GLP-1RAs) on the firing activity of nigral dopaminergic neurons and motor behaviors in MPTP-induced chronic PD mice. Our findings revealed that peripheral administration of GLP-1RAs exendin-4 significantly alleviated motor impairments in MPTP-induced chronic PD mice. Concurrently, peripheral administration of exendin-4 increased the number of active dopaminergic neurons, improved the spontaneous firing activity, as well as alleviated MPTP-induced dopaminergic neuron loss in MPTP-induced PD mice. Furthermore, local administration of exendin-4 directly increased the firing rate of nigral dopaminergic neurons via GLP-1Rs, suggesting that peripheral administration of exendin-4 may exert neuroprotection through its mild excitation on dopaminergic neurons. These findings collectively imply that peripheral administration of GLP-1RAs may hold potential in the treatment of PD.