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

Yazhou Li, Elliot J. Glotfelty, Inbar Namdar, David Tweedie, Lars Olson, Barry J. Hoffer, Richard D. DiMarchi, Chagi G. Pick, Nigel H. Greig

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number113113
JournalExperimental Neurology
Volume324
DOIs
StatePublished - Feb 2020

Keywords

  • Exendin-4
  • Glucagon (Gcg)
  • Glucagon-like peptide-1 (GLP-1)
  • Glucose-dependent insulinotropic polypeptide (GIP)
  • Incretin
  • Incretin mimetic
  • Mild traumatic brain injury
  • Neuroprotective
  • Neurotrophic
  • Triagonist

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