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Open Access 01-12-2024 | Tirzepatide | Research

Tirzepatide prevents neurodegeneration through multiple molecular pathways

Authors: Rosaria Anna Fontanella, Puja Ghosh, Ada Pesapane, Fatemeh Taktaz, Armando Puocci, Martina Franzese, Maria Federica Feliciano, Giovanni Tortorella, Lucia Scisciola, Eduardo Sommella, Concetta Ambrosino, Giuseppe Paolisso, Michelangela Barbieri

Published in: Journal of Translational Medicine | Issue 1/2024

Abstract

Background

Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders.

Methods

We investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures.

Results

For the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level.

Conclusions

We demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy.

Graphical Abstract

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Title: Tirzepatide prevents neurodegeneration through multiple molecular pathways
Authors: Rosaria Anna Fontanella
Puja Ghosh
Ada Pesapane
Fatemeh Taktaz
Armando Puocci
Martina Franzese
Maria Federica Feliciano
Giovanni Tortorella
Lucia Scisciola
Eduardo Sommella
Concetta Ambrosino
Giuseppe Paolisso
Michelangela Barbieri
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Tirzepatide
Insulins
Insulins
Type 2 Diabetes
Published in: Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-024-04927-z

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