Effects of fisetin on peroxynitrite concentration and amyloid content in the hypothalamus and cerebral cortex of rats with type 2 diabetes

Background: Diabetes is associated with neuronal oxidative and nitrosative stress and may alter amyloid-associated processes. Fisetin is a bioactive flavonoid with antioxidant and neuroprotective properties. This study evaluated the effects of fisetin on peroxynitrite concentration and amyloid fluorescence in the hypothalamus and cerebral cortex of control and diabetic rats.

Methods: Forty rats were assigned to four groups according to diabetes status (control or diabetic) and fisetin treatment (−/+), with 10 animals per group. Type 2 diabetes was induced by feeding rats a high-fat diet for 12 weeks and administering a single intraperitoneal dose of streptozotocin (35 mg/kg). During the subsequent 8 weeks, fisetin-treated animals received fisetin at 20 mg/kg/day by oral gavage. Peroxynitrite concentration and amyloid fluorescence were assessed in the hypothalamus and cerebral cortex. Effects of brain region, fisetin treatment, diabetes status, and their interactions were analyzed using three-way analysis of variance.

Results: Peroxynitrite concentration showed a significant brain-region effect (p<0.0001) and a significant diabetes × fisetin interaction (p=0.0070), whereas the main effects of diabetes (p=0.4422) and fisetin (p=0.4889) were not significant. Amyloid content differed significantly between brain regions (p=0.0001) and showed a significant brain region × diabetes interaction (p=0.0379). Neither the main effect of fisetin (p=0.2685) nor interactions involving fisetin were significant for amyloid fluorescence.

Conclusions: The effect of fisetin on cerebral peroxynitrite concentration depended on diabetes status rather than representing a uniform treatment effect. In contrast, amyloid content was primarily associated with brain region and its interaction with diabetes. These findings indicate distinct region- and disease-context-dependent responses of neuronal nitrosative and amyloid-associated processes to fisetin treatment.