PhD Scientific Days 2023

Pharmaceutical Sciences I.

Role of resveratrol in in vitro neuronal insulin signaling

Text of the abstract

Introduction: Brain insulin resistance has been associated with cognitive decline in several neurodegenerative diseases like Alzheimer’s disease, and improving insulin sensitivity could be a valuable target in its treatment. Resveratrol, a natural antioxidant compound has been shown to delay the loss of memory function in numerous age-related neurodegenerative diseases therefore considered as a neuroprotective agent. The underlying mechanisms, however are still unknown and the research on the effect of resveratrol on central insulin resistance is lacking.
Aim: Investigating the effect of resveratrol on central insulin signaling in our previously described in vitro neurodegeneration model.
Methods: Insulin resistance has been induced by 1mM streptozotocin in retinoic acid differentiated SH-SY5Y cells. Cell viability was measured with SRB reagent and Hoest/PI staining. The phosphorylation of IRS1, Akt, GSK3β, mTOR, and p70S6K were investigated with Western blot and ELISA-based microarray technique. The effect of resveratrol on mitochondrial biogenesis was assessed by measuring TFAM and ATP5B mRNA expression.
Results: Resveratrol concentration-dependently improved insulin induced proliferation in streptozotocin treated cells. It also decreased the Ser(312) phosphorylation of IRS1 commonly associated with insulin resistance and increased 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 transcription of mitochondrial transcriptional factor TFAM, and complex V subunit ATP5B and energy sensing AMPK, but resveratrol could reverse and further increase their expression.
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 includes 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.