Article

GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular an rodent model of stroke an Parkinsonism.

Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2009; 106(4):1285-90. DOI: 10.1073/pnas.0806720106
Source: PubMed

ABSTRACT Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic peptide secreted from the gastrointestinal tract in response to food intake. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus (T2DM). A long-acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first of this new class of antihyperglycemia drugs approved to treat T2DM. GLP-1Rs are coupled to the cAMP second messenger pathway and, along with pancreatic cells, are expressed within the nervous system of rodents and humans, where receptor activation elicits neurotrophic actions. We detected GLP-1R mRNA expression in both cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons. These cells are vulnerable to hypoxia- and 6-hydroxydopamine-induced cell death, respectively. We found that GLP-1 and Ex-4 conferred protection in these cells, but not in cells from Glp1r knockout (-/-) mice. Administration of Ex-4 reduced brain damage and improved functional outcome in a transient middle cerebral artery occlusion stroke model. Ex-4 treatment also protected dopaminergic neurons against degeneration, preserved dopamine levels, and improved motor function in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Our findings demonstrate that Ex-4 can protect neurons against metabolic and oxidative insults, and they provide preclinical support for the therapeutic potential for Ex-4 in the treatment of stroke and 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; DOI:10.1016/j.neuroscience.2015.06.054 · 3.33 Impact Factor
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    • "ing et al . , 2003 ; Abbas et al . , 2009 ; McClean et al . , 2010 , 2011 ; Han et al . , 2013 ) . In addition to acting on hip - pocampal cells , chronic treatment with GLP - 1 reduced degener - ation of dopaminergic neurons in the substantia nigra and led to an improvement in motor function ( Bertilsson et al . , 2008 ; Harkavyi et al . , 2008 ; Li et al . , 2009 ) . Although many preclinical studies suggest that GLP - 1R agonism can act directly on neurons"
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies.
    Frontiers in Neuroscience 03/2015; 9:92. DOI:10.3389/fnins.2015.00092 · 3.70 Impact Factor
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