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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    • "In preclinical studies, systemic administration of drugs for T2DM, such as insulin (Holscher, 2014b), rosiglitazone (Schintu et al., 2009), and metformin (Patil et al., 2014), significantly attenuate neuropathology, including the loss of SNpc neurons and the striatal Neuroprotective effects of D-­‐Ala2-­‐GIP-­‐GLU-­‐PAL 4 dopaminergic fibers, microglial activation, or the expression of pro-­‐inflammatory cytokines. Also, a drug that is on the market to treat type 2 diabetes, Exenatide (exendin-­‐4), showed a therapeutic effect in preclinical tests (Harkavyi et al., 2008; Kim et al., 2009; Li et al., 2009) and in a pilot clinical trial in PD patients (Aviles-­‐Olmos et al., 2013a; Aviles-­‐Olmos et al., 2014). In light of these recent findings, a hypothesis has emerged that suggests that mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and alterations in metabolism may lead to insulin resistance and, ultimately, to diabetes and/or neurodegeneration (Lima et al., 2014; Santiago and Potashkin, 2013). "
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    ABSTRACT: Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. Recent research has indicated a link between type 2 diabetes mellitus (T2DM) and PD, which suggested that a treatment to improve insulin resistance for T2DM may be useful for PD patients. Glucose-dependent insulinotropic polypeptide (GIP) belongs to the incretin hormone family, which can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. In the present study, a novel long-lasting GIP analogue, D-Ala2-GIP-glu-PAL, has been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. D-Ala2-GIP-glu-PAL treatment (25nmol/kg ip.) for 7 days after MPTP treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. D-Ala2-GIP-glu-PAL treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra and TH levels in the striatum. D-Ala2-GIP-glu-PAL also reduced the chronic inflammation response as seen in astrocyte and microglia activation in the substantia nigra pars compacta (SNpc). D-Ala2-GIP-glu-PAL reversed the reduction of synapse numbers (synaptophysin levels), decreased the ratio of growth factor and apoptosis signaling molecules Bax/Bcl-2, and improved the decrease of p-CREB(S133) growth factor signaling in the substantia nigra. Therefore, D-Ala2-GIP-glu-PAL promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB growth factor second messenger pathway that also inhibits apoptosis. The present results demonstrate that D-Ala2-GIP-glu-PAL shows promise as a novel treatment of PD.
    Neuropharmacology 10/2015; 101. DOI:10.1016/j.neuropharm.2015.10.002 · 5.11 Impact Factor
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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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