PhD Scientific Days 2024

Budapest, 9-10 July 2024

Pharmaceutical Sciences and Health Technologies I.

Resveratrol Restores Insulin Signaling in in vitro Streptozotocin Induced Neurodegenerative Model


Kamilla Varga1, Anna-Lena Friesenhahn2, Florian Emanuel Zymela2, Virag Kovacs3, Csenge Boroczky3, Noemi Sikur3, Alexandra Paszternak3, Tamas Tabi3, Stefan Wolfl2
1: Semmelweis Egyetem GyTK Gyógyszerhatástani Intézet
2: Institute for Pharmacy und Molecular Biotechnology, Ruprecht Karls University, Heidelberg
3: Department of Pharmacodynamics, Semmelweis University, Budapest

Text of the abstract

Introduction: Resveratrol, a natural phytoalexin, has been shown beneficial in age related disorders like Alzheimer’s disease. It has been proven to delay the loss of memory function and be considered as a neuroprotective agent. However, the underlying mechanisms are still unknown and the research on the effect of resveratrol on central insulin resistance is lacking. Addressing insulin sensitivity could hold significant therapeutic value in treating neurodegenerative conditions.
Aim: Examining the effect of resveratrol on insulin signaling and mitochondria in our previously described in vitro neurodegeneration model.
Methods: Insulin resistance has been induced by 1mM streptozotocin in retinoic acid differentiated neuron-like SH-SY5Y cells. Cell viability was assessed with SRB reagent. The phosphorylation of IRS1, Akt, GSK3β and mTOR were investigated by Western blot and ELISA-based microarray technique. The effect of resveratrol on mitochondrial biogenesis was assessed by Mitotracker staining and measuring TFAM and ATP5B mRNA expression.
Results: Resveratrol concentration-dependently improved insulin induced proliferation in streptozotocin treated cells. It also reduced the Ser(312) phosphorylation of IRS1 commonly associated with insulin resistance and decreased the IC50 value of Tyr(895) phosphorylation needed for activation. We observed similar insulin sensitizing effect on the components of downstream pathway; mTOR, p70S6K, Akt and GSK3β. Streptozotocin decreased the expression of mitochondrial transcriptional factor TFAM, complex V subunit ATP5B and energy sensing AMPK, and resveratrol could reverse these alterations and further increased their expression without altering the number of mitochondria.
Conclusion: Our results revealed that resveratrol can improve insulin signaling in streptozotocin induced insulin resistance even at its initial step of IRS1 phosphorylation. Its sensitizing effect include not only the metabolic effect, but the proliferative effect as well. The pathway may involve mitochondrial biogenesis and improving quality control.
Funding: Our project was funded by Semmelweis 250+ Excellence PhD Scholarship (EFOP-3.6.3-VEKOP-16-2017-00009) and Jellinek Harry Scholarship „Improvement of scientific workshops for medical, health science and pharmacy education” (EFOP-3.6.3.-VEKOP-16-2017-00009) with Ruprecht Karls University.