title: Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice.
abstract: Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pre-treatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were well-translated in a weight drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data cross-validate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI. Exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of traumatic brain injury (TBI). Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 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, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Tamargo
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.
authors.forename: Vardit
authors.initials: V
authors.lastname: Rubovitch
authors.affiliation: Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.affiliation: Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, 69978 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, USA.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000188:drug therapy; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000069450:Liraglutide / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: apoptosis; cAMP-response element binding protein; glucagon-like peptide-1; liraglutide; neuroprotection; traumatic brain injury