Troxerutin protects against high cholesterol-induced cognitive deficits in mice

Abstract

Recent findings suggest that neurotoxicity is the mechanism underlying the induction of neuronal insulin resistance by a high cholesterol diet. Troxerutin, a naturally occurring flavonoid, has been reported to possess biological activity beneficial to human health. Our recent studies have demonstrated that troxerutin attenuates cognitive impairment and oxidative stress induced by D-galactose in mouse brain through decreasing advanced glycation end products, reactive oxygen species and protein carbonyl levels and enhancing phosphoinositide 3-kinase/Akt activation. In this study, we evaluated the effect of troxerutin on cognitive impairment induced by brain insulin resistance in mice fed a high-cholesterol diet, and explored its potential mechanism. Our results showed that oral administration of troxerutin to these mice significantly improved behavioural performance in a step-through passive avoidance task and a Morris water maze task, at least in part, by decreasing the levels of reactive oxygen species, protein carbonyl and advanced glycation end products and blocking endoplasmic reticulum stress via reduced phosphorylation of the pancreatic endoplasmic reticulum-resident kinase and eukaryotic translation initiation factor 2α. Furthermore, troxerutin significantly inhibited the activation of c-jun N-terminal kinase 1 and IκB kinase β/nuclear factor-κB induced by endoplasmic reticulum stress and enhanced insulin signalling pathway, which prevented obesity, restored normal levels of blood glucose, fatty acids and cholesterol and increased the phosphorylation of cyclic adenosine monophosphate response element-binding protein and the expression levels of c-fos in the hippocampus. Moreover, troxerutin significantly inhibited endoplasmic reticulum stress-induced apoptosis and decreased the activation of caspase-12 and caspase-3, and reduced the mean optical density of the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end label-positive cells in the hippocampus. However, intra-cerebroventricular infusion of PI-103, a specific phosphoinositide 3-kinase 110α inhibitor, significantly inhibited the expression levels of phosphoinositide 3-kinase 110α and phosphoinositide 3-kinase downstream signalling in the hippocampus of mice co-treated with high cholesterol and troxerutin and vehicle control mice. These results suggest that troxerutin could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in type 2 diabetes mellitus and Alzheimer's disease.

Effect of Troxerutin on Cardiac Insulin Signaling in High Fat, High Fructose Diet - Induced Insulin Resistant Mice

“…Supplementation of TX enhanced IRβ and IRS-1 tyrosine phsphorylation, IRS-1-PI3K association thereby improves Akt activation in HFFDfed mice. Our findings are similar to that of Lu et al 26 reported that TX administration significantly improved insulin sensitivity in high-cholesterol-fed mice by increasing the serine phosphorylation of Akt which is due to activation of tyrosine phosphorylation of IR and IRS-1. Insulin induces the translocation of GLUT-4 from the intracellular storage to the sarcolemmal membrane and so favours glucose entry.…”

“…A study reported that that TX administration strongly inhibits the activation of JNK1 and IKKβ/NF-κB induced by endoplasmic reticulum stress in the hippocampus of highcholesterol-fed mice. 26 Further, our previous study also demonstrated the lipid-lowering effects of TX. 6 Akt/protein kinase B, a serine/threonine kinase is the downstream target of insulin signaling cascade that activates glucose uptake through GLUT-4.…”

“…6 Based on our previous finding that TX exhibits antihyperlipidemic activity by increasing the AMP-activated protein kinase phosphorylation, which, in turn, facilitates FA oxidation and FA transport in HFFD-fed mice, we strongly suggest that TX, being a potent antioxidant and antihyperlipidemic agent activates IRS-1-PI3K-Akt pathway thereby attenuate insulin resistance in HFFD-fed mice. TX administration have been shown to effectively improve insulin signaling in the hippocampus of mice -fed a high cholesterol diet 26 and in gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic adult male rat.…”

Troxerutin Counteracts Domoic Acid–Induced Memory Deficits in Mice by Inhibiting CCAAT/Enhancer Binding Protein β–Mediated Inflammatory Response and Oxidative Stress

“…A guillotine door separated the two compartments. The step-through test was conducted as previously described (31). In brief, the mice were placed in a dimly lit room, which contained the apparatus, for 0.5 h before training to allow the mice to acclimatize to their new environment.…”

“…Our previous studies have demonstrated that troxerutin has many different biological activities, including antioxidant and anti-inflammatory activities (27)(28)(29)(30)(31). Recently, our preliminary data showed that troxerutin blocked the phosphorylation of MAPK/ ERK1/2 (MEK1/2) in the hippocampus of DA-treated mice and reversed DA-induced memory deficits.…”