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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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

Funding

FundersFunder number
Ari and Regine Aprijaskis Fund
Dr. Miriam and Sheldon G. Adelson Center
Swedish Brain Foundation
Swedish Research Council K2012-62X-03185-42-4K2012-62X-03185-42-4
Tel-Aviv University
National Institutes of Health
National Institute on AgingR56AG057028
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Vetenskapsrådet
Tel Aviv University

    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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