Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease

Kyung Hee University, Sŏul, Seoul, South Korea
Journal of Endocrinology (Impact Factor: 3.72). 09/2009; 202(3):431-9. DOI: 10.1677/JOE-09-0132
Source: PubMed


Exendin-4 is a naturally occurring more potent and stable analog of glucagon-like peptide-1 (GLP-1) that selectively binds at the GLP-1 receptor. It has been recently demonstrated that GLP-1 receptor stimulation preserves dopaminergic neurons in cellular and rodent models of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity in rodents; previous studies suggest that activated microglia actively participate in the pathogenesis of PD neurodegeneration. However, the role of microglia in the neuroprotective properties of exendin-4 is still unknown. Here, we show that, in the mouse MPTP PD model, systemic administration of exendin-4 significantly attenuates the loss of substantia nigra pars compacta (SNpc) neurons and the striatal dopaminergic fibers. Exendin-4 prevents MPTP-induced microglial activation in the SNpc and striatum, and the expression of matrix metalloproteinase-3. In addition, exendin-4 also suppressed MPTP-induced expression of pro-inflammatory molecules and tumor necrosis factor alpha and interleukin-1 beta. Our data indicate that exendin-4 may act as a survival factor for dopaminergic neurons by functioning as a microglia-deactivating factor and suggest that exendin-4 may be a valuable therapeutic agent for neurodegenerative diseases such as PD.

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    • "The recently-published Exenatide pilot clinical trial [18] apart from its clinical findings, also demonstrated the feasibility [19] of running a learning trial in a relatively small number of PD patients. Exenatide is an intervention originally targeted at Diabetes Type II but which was thought a priori to offer considerable potency and potential clinical benefit in the treatment of PD [20] [21] [22] [23] [24] [25]. "
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    • "MPTP (1-methyl-4-phe nyl-1,2,3,6-tetrahydropyridine is a neurotoxin precursor to 1-methyl-4-phenylpyridinium (MPP+), which induces classic symptoms of Parkinson's disease by impairing or destroying dopaminergic neurons in the substantia nigra (Nakamura and Vincent, 1986; Gerlach et al., 1991). MPTP is a widely used chemical to induce a Parkinsonlike state in animals (Nakamura and Vincent, 1986; Kopin and Markey, 1988; Kim et al., 2009; Li et al., 2009). "
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    ABSTRACT: Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p.. When comparing exendin-4 (10nmol/kg), liraglutide (25nmol/kg) and lixisenatide (10nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP- induced motor impairment (Rotarod, open field locomotion, catalepsy test), reduction in Tyrosine Hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule Bcl-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 06/2015; 303. DOI:10.1016/j.neuroscience.2015.06.054 · 3.36 Impact Factor
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    • "In contrast, GLP-1 induced morphological changes in microglia and inhibited LPS-induced IL-1β, IL-6 and inducible NOS production in cultured astrocytes (Iwai et al., 2006). In addition, exenatide reduced MPTP-stimulated expression of TNF-α and IL-1β (Kim et al., 2009). It has been hypothesized that WB4-24 produces antinociception in part by inhibiting the expression of cytokines. "
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