title: Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke.
abstract: Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB.
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address: liyaz@mail.nih.gov.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Kou-Jen
authors.initials: KJ
authors.lastname: Wu
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Tamargo
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address: greign@mail.nih.gov.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053772:Oxyntomodulin / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D053772:Oxyntomodulin; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D050882:CREB-Binding Protein
keywords: Glucagon receptor; Glucagon-like peptide-1 receptor; Glutamate excitotoxicity; Neuroprotection; Oxidative stress; Oxyntomodulin; Stroke