title: Novel GLP-1R/GIPR co-agonist "twincretin" is neuroprotective in cell and rodent models of mild traumatic brain injury.
abstract: Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed "twincretin," was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: iatamargo@gmail.com.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Tamargo
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Miaad
authors.initials: M
authors.lastname: Bader
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: Greign@mail.nih.gov.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000188:drug therapy*; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006801:Humans; D054795:Incretins / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008813:Mice, Inbred ICR; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011964:Receptors, Gastrointestinal Hormone; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor; D050882:CREB-Binding Protein; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Glucagon-like peptide-1; Glucose-dependent insulinotropic peptide; Incretin; Incretin mimetic; Neurodegeneration; Traumatic brain injury