Influence of fisetin combined with hesperidin on chronic mild hyperhomocysteinemia induced cognitive dysfunction and oxidative stress in wistar rats

Hyperhomocysteinemia is a genetic disorder charecterized by elevated levels of homocysteine in the blood (> 15 mu M). This study was aimed to evaluate the neuroprotective role of fisetin and hesperidin on homocysteine induced chronicmild hyperhomocysteinemia in wistar rats. DL-homocysteine (0.03 mu moL/g/ b.w,s.c.twice a day) administration from 30th-62nd postpartum day in rats induced chronic mild hyperhomocysteinemia. Rats were then evaluated for cognitive dysfunction, oxidative/nitrative stress and several biochemical as well as morphological parameters of brain cortex and hippocampus. Our results indicate that chronic mild hyperhomocysteinemia induced cognitive impairment, increased serum homocysteine, brain acetylcholinesterase, lipidperoxidation, TNF-alpha, IL-6 and myeloperoxidase levels. In addition decrease in brain nitrite, superoxide dismutase, catalase, reduced glutathione, brain-derived neurotrophic factor and mitochondrial respiratory complexes, resulted in necrotic foci and marked neurodegeneration in cortex and hippocampus regions. Our findings show that fisetin and hesperidin treatment prevented behavioral deficits, increased brain antioxidant and nitrite levels, reduced serum homocysteine, pro-inflammatory biomarkers, lipid peroxidation, cholinergic and mitochondrial dysfunction and reduced histological abberrations. Fisetin in combination with hesperidin showed better potency in neuroprotection against chronic mild hyperhomocysteinemia. Overall this study reveals fisetin and hesperidin as potential therapeutic targets for homocysteine induced hyperhomocysteinemia.