الفهرس 
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Abstract
Objective. The aim of our work was to investigate potential protective effects of febuxostat, a highly potent xanthine oxidase inhibitor with antioxidant effect, and/or changing life style (stopping high fat diet) on atherosclerosis induced by high-fat diet (HFD) in rabbits.research design and Methods. Male New Zealand White rabbits were fed standard chow (Normal control;NC), high-fat diet with 1% cholesterol for 8 weeks (HFD 8), high-fat diet with 1% cholesterol for 8 weeks then shifting to standard chow plus oral administration of vehicle 0.5% CMC for 4 weeks (HFD 12), high-fat diet with 1% cholesterol for 8 weeks then shifting to standard chow plus oral administration of febuxostat with doses 2, 5 and 10 mg/kg/day for 4 weeks (FX 2, FX 5, FX 10 groups). Blood samples were collected after 8 and 12 weeks. The extent of aortic atherosclerosis was measured. Lipid profile, , lipid peroxidation index (malondialdehyde; MDA), antioxidant activity (superoxide dismutase, catalase and glutathione reduced), pro-inflammatory cytokines (IL-1β, TNF-α and nitric oxide) and pro-atherogenic molecules (ICAM-1 and VCAM-1) were measured. Results. Eight weeks on high-fat diet elevated all bad lipids; total cholesterol (by 13 fold), triglycerides (by 4 fold), low-density lipoprotein (by 66 fold), very low-density lipoprotein (by 4 fold), and caused the good high-density lipoprotein to DROP (by 1.6 fold). Inflammation and oxidative stress markers were all elevated; serum malondialdehyde (by 11 fold), serum interleukin-1 beta (by 2 fold), serum tumor necrosis factor-α (by 2fold), serum nitrite (by 6 fold), serum intercellular adhesion molecule-1 (by 3 fold), serum vascular cell adhesion molecule-1 (by 3 fold). Antioxidant defense enzymes were decreased; serum superoxide dismutase (by 1.4 fold), serum glutathione reduced (by 1.7 fold). Histological changes of aortic tissues were significant. the percent of plaque area was 19.5% of the total aortic arch. The aortic intima/media thickness ratio was 0.36. The intimal surface showed a remarkable atheromatous plaque (Type IV lesion). Febuxostat (dose 2 mg) significantly lowered the total cholesterol (by 2 fold), triglycerides (by 3 fold), LDL (by 3 fold), VLDL (by 3 fold). The HDL has been enhanced (by 1.3 fold). Febuxostat also displayed a potent anti-inflammatory and antioxidant activity by decreasing serum and tissue levels of MDA, IL-1β, TNF-α and enhancing GSH and SOD activity. Febuxostat reduced plaque formation, so the aortic I/M ratio was 12 fold less and the aortic section was close to normal. Other febuxostat doses (5 and 10 mg/kg/day) showed less progression than dose 2 mg, this is probably due to drug-induced hepatotoxicity. Stopping atherogenic diet after 8 weeks of induction of atherosclerosis and shifting to standard diet without treatment (HFD 12) didn’t cause any improvement, it showed a significant deterioration in all biological markers instead. Conclusions. These findings suggest antioxidant and anti-inflammatory effects of febuxostat that may be common mechanisms of antiatherosclerotic effect of this drug. The hepatotoxicity of febuxostat urges further investigation to determine the toxicity threshold.