Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats

Abstract

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes’s impairment of spatial learning memory.Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines.Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide.Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

Tirzepatide prevents neurodegeneration through multiple molecular pathways

“…Our results agree with previous data showing that TIR significantly activated PI3K/AKT/GSK3β signaling pathway ameliorating insulin resistance in the hippocampus of diabetic rats [ 25 ].…”

“…A novel drug, TIR has been recently synthesized, able to bind both GLP-1 and GIP incretin receptors and with a stronger effect in decreasing glycated hemoglobin and in improving systemic insulin sensitivity in T2DM, when compared to the GLP-1RA [ 14 , 17 ]. So far, a potential protective effect against spatial learning and memory impairment has been, only recently, addressed in diabetic mice [ 25 ] but, the molecular processes involved remain unknown.…”

“…Indeed, although GIP and GLP-1 share many common actions in the pancreas, they have been shown to have distinct actions outside of the pancreas [ 18 ], and the potential role of TIR on neuroprotection has never been investigated. More recently, a potential protective effect of TIR against spatial learning and memory impairment has been very recently demonstrated in diabetic mice [ 25 ] but no data on the molecular processes involved were provided.…”

Bridging the gap between GLP1-receptor agonists and cardiovascular outcomes: evidence for the role of tirzepatide

“…This suggests that tirzepatide may have cardioprotective benefits by acting as an anti-inflammatory agent [ 67 ]. Furthermore, tirzepatide therapy in diabetic rats restored specific abnormal alterations in signal molecules related to inflammatory signaling pathways via PI3K/Akt/GSK3β signaling pathway [ 68 ].…”