Troxerutin

The fruits of Styphnolobium japonicum (L.) Schott

Troxerutin can also offer protection against DNA strand breaks and micronuclei formation induced by γ–radiation (GR), it enhances repair of DNA strand breaks induced by radiation. In lymphocytes, treatment with 1mM troxerutin significantly decreased the induction of micronuclei resulted from the exposure to 2 Gy γ-radiation by 41.26% [1].

GR can induce cellular damage and apoptosis. It can cause double-stranded and single-stranded breaks in the genomic DNA [2].

Under ex vivo condition of GR (2 Gy), DNA strand breaks were induced by the radiation. Treatment with troxerutin protected the human peripheral blood leucocytes from this GR effect. In the human lymphocytes, the micronuclei induction resulted from GR was significantly inhibited by troxerutin (1 mM) [1].

In mice, micronuclei formation in blood reticulocytes was significantly inhibited by the intraperitoneal administration of troxerutin (175 mg/kg) before and after whole body radiation exposure. 1 h prior to 4 Gy γ -radiation exposure, in bone marrow cells and blood leucocytes, the yield of DNA strand breaks was dose-dependently decreased by the administration of troxerutin at different doses (75, 125 and 175 mg/kg body weight). The dose-dependent protection was less pronounced in blood leucocytes than in bone marrow cells. In mice, 1 h prior or immediately after whole body irradiation, administration of troxerutin at 175 mg/kg body weight (i.p.) decrease the strand breaks depended on the post-irradiation interval [1].

References:
[1].  Maurya DK, Balakrishnan S, Salvi VP, et al. Protection of cellular DNA from gamma-radiation-induced damages and enhancement in DNA repair by troxerutin. Mol Cell Biochem, 2005, 280(1-2):57-68.
[2].  Chen YR, Meyer CF and Tan TH. Persistent Activation of c-Jun N-terminal Kinase 1 (JNK1) in γ Radiation-induced Apoptosis. J Biol Chem, 1996, 271(2): 631–634.

Troxerutin protects against high cholesterol-induced cognitive deficits in mice.[Pubmed:21252113]

Brain. 2011 Mar;134(Pt 3):783-97.

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 2alpha. Furthermore, Troxerutin significantly inhibited the activation of c-jun N-terminal kinase 1 and IkappaB kinase beta/nuclear factor-kappaB 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 110alpha inhibitor, significantly inhibited the expression levels of phosphoinositide 3-kinase 110alpha 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.

Efficacy of troxerutin on streptozotocin-induced rat model in the early stage of diabetic retinopathy.[Pubmed:16294503]

Arzneimittelforschung. 2005;55(10):573-80.

The vascular changes associated with early diabetic retinopathy, which include the formation of microaneurysms and acellular capillaries, vessel dilation, vascular endothelial growth factor expression, were investigated experimentally in streptozotocin-induced diabetic rats treated with antioxidants: Troxerutin (trihydroxy-ethylrutoside, CAS 7085-55-4), Vaccinium myrtillus, and calcium dobesilate (hydroquinone calcium sulfonate, CAS 20123-80-2). The development and progression of retinopathy was followed using fundus photography. After 3 months, the rats were sacrificed and half of the eyes were prepared for neovascularization analysis, and the other half were used for VEGF (vascular endothelial growth factor) analysis. The results from fundus photography and ADPase (adenosine diphosphatase) staining were quantified by the percentage area of the retinal vasculature using a commercial image analyzer. The VEGF protein in the retinal homogenates was assessed using an ELISA (enzyme linked immunosorbent assay) kit and VEGF-mRNA by RT-PCR (reverse transcription polymerase chain reaction). In the ADPase stain, the retinal vascular percent area increased significantly in the diabetic control. Neovascularization and aneurysms were observed in the diabetic control and were attenuated by 50 mg/kg Troxerutin, but the retinal vascular percentage area was not significantly different from the diabetic control. The VEGF protein concentration was higher in diabetic rats than in the nondiabetic rats (21.5 +/- 2.1 vs 27.7 +/- 5.8 pg/mg, p < 0.05), and this increase was attenuated by 10 mg/kg Troxerutin (24.5 +/- 3.8 pg/mg, p < 0.05) and prevented by 50 mg/kg Troxerutin (19.5 +/- 2.2 pg/mg, p < 0.05). However, there were no significant differences between the groups. The VEGF-mRNA density showed a increasing tendency by 20% in the diabetic rats compared with the non-diabetic rats (1.0 +/- 0.1 vs 1.2 +/- 0.1 VEGF/beta-actin), and this increase was corrected by 10 mg/kg Troxerutin (1.0 +/- 0.1 VEGF/beta-actin), 50 mg/kg Troxerutin (0.9 +/- 0.1 VEGF/beta-actin) and Vaccinium myrtillus (1.1 +/- 0.1 VEGF/beta-actin). Oxidative stress might be involved in the upregulation of retinal VEGF during early diabetes, and it is likely that Troxerutin has comparatively effective antioxidant properties. Therefore, Troxerutin might be a useful treatment for attenuating diabetic retinopathy.

Troxerutin protects the mouse kidney from d-galactose-caused injury through anti-inflammation and anti-oxidation.[Pubmed:19000936]

Int Immunopharmacol. 2009 Jan;9(1):91-6.

This study was carried out to investigate the protective effect of Troxerutin against D-galactose (D-gal)-induced renal injury in mice. Hematoxylin and eosin (H&E) stained sections of kidneys revealed D-gal could cause renal injury and Troxerutin could significantly attenuate the injury. We further investigated the mechanisms involved in the protective effects of Troxerutin on mouse kidney. The following antioxidant defense enzymes were measured: cytosolic Cu/Zn superoxide dismutase (SOD-1), catalase (CAT) and glutathione peroxidase (GPx). The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. In D-gal-treated mice, antioxidant enzymes activities were significantly decreased and the level of MDA was significantly higher than those in the vehicle controls. Our results indicated that the protective effect of Troxerutin against D-gal induced renal injury might be caused, at least in part, by increasing the activity of antioxidant enzymes with a reduction in lipid peroxidation product. Furthermore, we also examined the inflammatory signal mediators of nuclear factor-kappaB (NF-kappaB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanoid receptor subtype EP2 by Western blot. After treatment with D-gal, the NF-kappaB p65, iNOS, COX-2 and EP2 were markedly upregulated. Upon co-treatment with the Troxerutin, however, the expressions of the NF-kappaB p65, iNOS, COX-2 and EP2 markedly reduced, compared to D-gal treatment alone. These results indicated that Troxerutin has significantly inhibitory effects on the NF-kappaB-mediated inflammatory response. These findings suggest Troxerutin could attenuate renal injury induced by D-gal probably through its antioxidant and anti-inflammation properties.

Troxerutin, also known as vitamin P4, is a tri-hydroxyethylated derivative of natural bioflavonoid rutins which can inhibit the production of reactive oxygen species (ROS) and depress ER stress-mediated NOD activation.

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