Article ; Online: Tirzepatide prevents neurodegeneration through multiple molecular pathways.
Journal of translational medicine
2024 Volume 22, Issue 1, Page(s) 114
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 ... ...
| 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. |
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| MeSH term(s) | Humans ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Insulin/metabolism ; Insulin Resistance ; Brain-Derived Neurotrophic Factor ; Blood Glucose/metabolism ; MicroRNAs ; Glucagon-Like Peptide-1 Receptor/agonists ; Hypoglycemic Agents/pharmacology ; Glucagon-Like Peptide-2 Receptor ; Gastric Inhibitory Polypeptide |
| Chemical Substances | tirzepatide (OYN3CCI6QE) ; Insulin ; Brain-Derived Neurotrophic Factor ; Blood Glucose ; MicroRNAs ; Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents ; MIRN212 microRNA, human ; Glucagon-Like Peptide-2 Receptor ; Gastric Inhibitory Polypeptide (59392-49-3) |
| Language | English |
| Publishing date | 2024-01-29 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2118570-0 |
| ISSN | 1479-5876 ; 1479-5876 |
| ISSN (online) | 1479-5876 |
| ISSN | 1479-5876 |
| DOI | 10.1186/s12967-024-04927-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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