Research PaperNovel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

- The dual GLP-1/GIP receptor agonist “twincretin” was evaluated for neurotrophic and neuroprotective actions in cell and in vivo models of mild TBI.
- Twincretin provided neurotrophic properties in immortal human SH-SY5Y neuronal cells - elevating cAMP levels and pCREB.
- Twincretin provided neuroprotection against oxidative stress and glutamate excitotoxicity in human SH-SY5Y cells.
- Twincretin protected rat primary cultures of dopaminergic ventral mesencephalon neurons from 6-hydroxydopamine-induced injury.
- A clinically translatable dose of twincretin fully mitigated mild TBI-induced spatial and visual memory deficits in a mouse close head injury model.
- Twincretin mediated mitigation of cellular and in vivo TBI-induced impairments highlight the agent for evaluation in neurodegenerative disorders.

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed “twincretin,” was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.

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