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.
Romagnoli
Marco
M
Catholic University of Valencia, Spain.
Gomez-Cabrera
Mari-Carmen
MC
Perrelli
Maria-Giulia
MG
Biasi
Fiorella
F
Pallardó
Federico V
FV
Sastre
Juan
J
Poli
Giuseppe
G
Viña
Jose
J
D000493:Allopurinol / Q000008:administration & dosage* / Q000627:therapeutic use; D000496:Alloxan / Q000008:administration & dosage; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D018384:Oxidative Stress; D011141:Polyuria; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000008:administration & dosage; D015533:Transcriptional Activation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism*
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D013311:Streptozocin; D000493:Allopurinol; D000496:Alloxan; D014969:Xanthine Oxidase