PhD Scientific Days 2025

Pharmaceutical Sciences and Health Technologies III.

Neuronal Insulin-Sensitizing Effects of Resveratrol Derivatives in vitro

Name of the presenter

Varga Kamilla

Institute/workplace of the presenter

Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary

Authors

Kamilla Varga¹, Noemi Sikur¹, Rama Jazmin Gyongyossy¹, Alexandra Paszternak¹, Stefan Wolfl²

1: Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
2: Institute of Pharmacy and Molecular Biotechnology, Ruprecht Karls University, Heidelberg, Germany

Text of the abstract

Introduction: Resveratrol, a polyphenolic compound with antioxidant and neuroprotective properties, has shown potential in mitigating memory loss. However, its precise mechanisms, particularly concerning central insulin resistance, remain unclear. Our recent findings suggest that resveratrol enhances insulin signaling by promoting IRS1 phosphorylation and activating downstream pathways, potentially through improved mitochondrial quality via biogenesis and mitophagy.
Aim: This study aimed to investigate how structural modifications of stilbene derivatives influence their protective effects in a neuronal insulin resistance model.
Methods: Insulin resistance was induced in differentiated SH-SY5Y cells using 1 mM streptozotocin. Cells were concurrently treated with 10 μM resveratrol or its derivatives: oxy- (Oxy), monomethyl (Mono), and trimethyl resveratrol (Tri). Mitochondrial membrane potential and ROS production were assessed using JC-1, and DCFDA/HE staining respectively.Insulin signaling was assessed by phospho-GSK3 ELISA and LDH assay under varying insulin concentrations. Protein aggregation was detected using Thioflavin T staining.
Results: Resveratrol and its analogues enhanced insulin sensitivity in a structure-dependent manner. The EC50 for insulin's cytoprotective effect improved from 544.8 μM to a range of 15–200 μM, depending on the compound. The antioxidant properties of the compounds corraleted strongly with their respective oxidative status. Notably, resveratrol and its methylated derivatives, especially Tri- (EC50 = 1.17 μM), significantly increased mitochondrial polarization, whereas Oxy- showed minimal effect. Moreover, all derivatives reduced misfolded protein accumulation.
Conclusion: Resveratrol and its analogues effectively mitigated certain pathological processes associated with Alzheimer’s disease, such as insulin resistance, protein aggregation and mitochondrial dysfunction. Oxy showed the strongest antioxidant effect accompanied by the most effective insulin sensitizing action.
Funding: This research was supported by the Semmelweis 250+ Excellence PhD Scholarship, Jellinek Harry Scholarship in collaboration with Ruprecht Karls University, and the 2024-2.1.1-EKÖP-2024-0004 (203) University Research Scholarship Programme of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund.