Tirzepatide prevents neurodegeneration through multiple molecular pathways
Open accessAbstract
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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Tirzepatide's neuroprotective outcomes remain clinically unconfirmed, but it has shown favorable cardiometabolic and neuroprotective outcomes in cellular models.
“Although tirzepatide's neuroprotective outcomes remain clinically unconfirmed, it has shown favorable cardiometabolic and neuroprotective outcomes in cellular models.22,23”
From Neurodegeneration and Stroke After Semaglutide and Tirzepatide in Patients With Diabetes and Obesity (2025) · cites this paper as [23]
The Background describes experiments in a human neuroblastoma cell line, and the Conclusions report neuroprotective effects while stating that clinical studies are needed to validate the in vitro results. The Discussion also reports improved neuronal glucose homeostasis, but it does not establish favorable cardiometabolic outcomes in the cellular model; its discussion of systemic metabolic benefits concerns people with type 2 diabetes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTirzepatide activates Akt/CREB/BDNF pathway and downstream signaling cascade counteracting hyperglycemia and insulin resistance-related damage at the neuronal level.
“Similarly, Fontanella RA et al. demonstrated that in neuronal cells that tirzepatide activates Akt/CREB/BDNF pathway and the downstream signaling cascade counteracting hyperglycemia and insulin resistance-related damage at the neuronal level (51).”
From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [51]
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- Authors
- Fontanella, R. A., Ghosh, P., Pesapane, A., Taktaz, F., Puocci, A., Franzese, M., Feliciano, M. F., Tortorella, G., Scisciola, L., Sommella, E., Ambrosino, C., Paolisso, G., & Barbieri, M.
- Affiliations
- University of Campania "Luigi Vanvitelli" (IT)
- University of Salerno (IT)
- University of Sannio (IT)
- Corresponding author
- Scisciola, Lucia
- ORCID
- Venue
- Journal of Translational Medicine
- Published
- 2024-01-29
- Volume
- 22
- Issue
- 1
- Pages
- 114-114
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC10823712
- OpenAlex
- W4391317038
- Cited by
- 67
- References
- 66
- Citations by year
- 2026: 19 · 2025: 37 · 2024: 11
- FWCI
- 19.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- AdvaNced Technologies for Human-centrEd Medicine (PNC0000003)
- Ministero dell′Istruzione, dell′Università e della Ricerca Scientifica (2017CPLH3)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tirzepatide, neuroprotection, neurodegeneration, GLP-1 receptor agonists, GIP receptor agonist, type 2 diabetes, hyperglycemia, insulin resistance, neuronal apoptosis, Akt signaling, DNA methylation, microRNA, diabetic neuropathy, learning and memory, SH-SY5Y cells
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-2 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Blood Glucose, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Brain-Derived Neurotrophic Factor, MicroRNAs
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