Sirtuins, redox, and metabolic pathways in the brain of female PCOS mice

Purpose: Recent studies emphasize the role of neuroendocrine dysfunctions and sirtuins in polycystic ovarian syndrome (PCOS). We investigated whether altered SIRT1 and SIRT3 levels contribute to brain changes and oxidative stress, identifying these pathways as potential therapeutic targets for PCOS-related complications. Methods: Using a DHEA-induced PCOS mouse model, we examined brain expression of pathways related to SIRT1 and SIRT3 and to oxidative/glycative stress changes. SH-SY5Y cells treated with DHEA were used to confirm direct neuronal effects. Results: We found decreased levels of Sirt1 and Sirt3 transcripts but increased protein expression and activity of both sirtuins in brains of DHEA-treated mice. The DHEA group showed elevated oxidative and glycative stress, including an overall increased lipid peroxidation and DNA damage, as well as accumulation of advanced glycation endproducts (AGEs) in isocortices. Differences in Cpt1 isoform expressions suggested disrupted metabolic processing in the PCOS brains. Neuronal degeneration was also observed, alongside unchanged Bdnf and TrkB mRNA levels in DHEA brains. Exposure of differentiated SH-SY5Y neuron-like cells to high concentrations (≥ 100 µM) led to increased oxidative stress, altered sirtuins expression, and ultimately cell toxicity. While low concentrations of DHEA (1 µM) did not elicit such responses. Conclusions: These findings reveal a complex interplay between oxidative stress, metabolic dysregulation, and neuronal health in PCOS brain, underscoring the need for further investigations into the underlying mechanisms, including research in genetic components. This research provides foundational insights into how PCOS may influence neurobiological processes and helps clarify some aspects of its pathogenesis.