Pterostilbene Ameliorates Cognitive Impairment in Polycystic Ovary Syndrome Rat Model through Improving Insulin Resistance via the IRS-1/PI3K/Akt/GSK-3β Pathway: A Comparative Study with Metformin.
Aliaa M FodaSafinaz S IbrahimSherehan M IbrahimEman Maher ElbazPublished in: ACS chemical neuroscience (2024)
Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer's disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3β insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3β pathway, reducing GSK-3β activity, and mitigating Tau hyperphosphorylation and Aβ accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.
Keyphrases
- polycystic ovary syndrome
- pi k akt
- signaling pathway
- insulin resistance
- cell cycle arrest
- cell proliferation
- nuclear factor
- cognitive impairment
- type diabetes
- high fat diet
- adipose tissue
- epithelial mesenchymal transition
- metabolic syndrome
- induced apoptosis
- skeletal muscle
- glycemic control
- oxidative stress
- white matter
- cognitive decline
- pregnant women
- tyrosine kinase
- high fat diet induced
- subarachnoid hemorrhage
- mild cognitive impairment
- human health
- weight loss
- mouse model
- inflammatory response
- risk assessment
- resting state
- immune response
- molecular dynamics