Xanthine oxidase-induced oxidative stress causes activation of NF-kappaB and inflammation in the liver of type I diabetic rats.

We previously showed that xanthine oxidase activity increases in type I diabetic animals and that this is a significant cause of the oxidative stress which occurs in the disease. The aim of this work was to search for molecular links between xanthine oxidase-induced oxidative stress and inflammation in Type I diabetes and to assess the ability of allopurinol, a drug widely used in clinical practice, to prevent both processes. 3-month-old male Wistar rats were made diabetic by injection (i.p.) of either streptozotocin or alloxan. Allopurinol (32 mg/Kg) was administered (i.p) to diabetic rats after they had shown clear signs of diabetes such as glucosuria and polyuria. Hepatic phospho-IKKbeta and phospho-IkappaBalpha contents were increased in diabetic animals. This was accompanied by increased levels of NF-kappaB (p65 protein content) in liver nuclear extracts. Hepatic expression of NF-kappaB dependent inflammatory cytokines and enzymes, namely interleukin 1beta, iNOS and interleukin 6 were markedly increased. Both diabetes-induced activation of NF-kappaB signalling cascade and subsequent over expression of inflammatory cytokines and enzymes were abolished by administration of allopurinol. Moreover, we found a significant neutrophil infiltration in the liver of diabetic animals. These events were also prevented by administration of allopurinol.