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Exp Neurol ; 324: 113113, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31730763

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/agonistas , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Linhagem Celular , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ácido Glutâmico/toxicidade , Humanos , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/administração & dosagem , Nootrópicos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos
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