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      Neuroprotective Effects of Liraglutide for Stroke Model of Rats

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          Abstract

          The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson’s test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

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          The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease.

          Paula L. McClean, Vadivel Parthsarathy, Emilie Faivre … (2011)
          Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP(swe)/PS1(ΔE9) (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40-50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.
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            GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism.

            Yazhou Li, TracyAnn Perry, Mark Kindy … (2009)
            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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              Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

              Kerry Hunter, Christian Hölscher (2012)
              Background Type 2 diabetes is a risk factor for Alzheimer's disease (AD), most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza) and exenatide (Byetta) are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R). Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. Results In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza) and lixisenatide (Lyxumia). We measured the kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. Conclusions Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of neurodegenerative diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1422-0067
                Publication date Collection: November 2013
                Publication date (Electronic): 30 October 2013
                Volume: 14
                Issue: 11
                Pages: 21513-21524
                Affiliations
                [1 ]Department of Neurological Surgery, Okayama University Graduate School of Medicine, Okayama 700-8558, Japan; E-Mails: satoken645@ 123456gmail.com (K.S.); mrkameda@ 123456gmail.com (M.K.); agarit@ 123456cc.okayama-u.ac.jp (T.A.); shinkoaiko@ 123456gmail.com (A.S.); wakagon@ 123456cc.okayama-u.ac.jp (T.W.); atsuhiko.t@ 123456kyj.biglobe.ne.jp (A.T.); tacken_osyo_fd3s_in_motion@ 123456yahoo.co.jp (H.T.); tatu_tatu_sasa@ 123456yahoo.co.jp (T.S.); sasadaminami@ 123456yahoo.co.jp (S.S.); domacv@ 123456yahoo.co.jp (A.K.); idate333@ 123456md.okayama-u.ac.jp (I.D.)
                [2 ]Department of Neurosurgery, Tokai University, Tokyo 151-0063, Japan; E-Mails: babatane@ 123456is.icc.u-tokai.ac.jp (T.B.); mike@ 123456is.icc.u-tokai.ac.jp (M.M.)
                [3 ]Center for Innovative and Translational Medicine, Kochi University Medical School, Nankoku 783-8505, Japan; E-Mail: f-wang@ 123456kochi-u.ac.jp
                [4 ]Department of Neurosurgery, University of South Florida College Medicine, Tampa, FL 12901, USA; E-Mail: cborlong@ 123456health.usf.edu
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: tyasu37@ 123456cc.okayama-u.ac.jp ; Tel.: +81-86-235-7336; Fax: +81-86-227-0191.
                Article
                Publisher ID: ijms-14-21513
                DOI: 10.3390/ijms141121513
                PMC ID: 3856019
                PubMed ID: 24177570
                SO-VID: 804b90e8-ccc5-429f-a978-1780184b3853
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 02 September 2013
                Date revision received : 18 October 2013
                Date accepted : 23 October 2013
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: cerebral ischemia,diabetes mellitus,glucagon-like peptide-1,liraglutide,oxidative stress,stroke,vegf
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: cerebral ischemia, diabetes mellitus, glucagon-like peptide-1, liraglutide, oxidative stress, stroke, vegf

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