Neurotrophic and neuroprotective effects of a monomeric GLP-1/GIP/Gcg receptor triagonist in cellular and rodent models of mild traumatic brain injury.

Abstract

A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7 days, to mice following a 30 g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30 days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy.

• Authors: Yazhou Li, Elliot J Glotfelty, Inbar Namdar, David Tweedie, Lars Olson, Barry J Hoffer, Richard D DiMarchi, Chagi G Pick, Nigel H Greig
• Journal: Experimental neurology (Exp Neurol) Vol. 324 Pg. 113113 (02 2020) ISSN: 1090-2430 [Electronic] United States
• PMID: 31730763 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Inc.

Chemical References

• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Neuroprotective Agents
• Nootropic Agents
• Glutamic Acid
• Gastric Inhibitory Polypeptide
• Glucagon
• Cyclic AMP

Topics

• Animals
• Brain Injuries, Traumatic (drug therapy, psychology)
• Cell Line
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Gastric Inhibitory Polypeptide (agonists)
• Glucagon (agonists)
• Glucagon-Like Peptide-1 Receptor (agonists)
• Glutamic Acid (toxicity)
• Humans
• Injections, Subcutaneous
• Male
• Mice
• Mice, Inbred ICR
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Nootropic Agents (administration & dosage, therapeutic use)
• Oxidative Stress (drug effects)
• Space Perception (drug effects)
• Visual Perception (drug effects)