Pentoxifylline reduces the inflammatory process in diabetic rats: relationship with decreases of pro-inflammatory cytokines and inducible nitric oxide synthase

Studies suggest that inflammation is a key factor in the pathogenesis of diabetes mellitus. Pro-inflammatory cytokines, such as IL-6 and TNF-alpha, are produced by adipose tissue in large quantities, in obese and especially in diabetic individuals. Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor with anti-inflammatory and antioxidant actions that may contribute to alleviate diabetes side effects, as neuropathy, retinopathy and nephropathy. This study aims to investigate PTX anti-inflammatory effects on the carrageenan-induced paw edema model, in alloxan-induced diabetic rats. Diabetic animals (male Wistar rats, 200-250 g) were daily treated with PTX (25, 50, 100 mg/kg, p.o.), glibenclamide (GLI, 5 mg/kg, p.o., as reference) or water, for 5 days. Afterwards, carrageenan-treated paws were dissected, their skin removed and the tissue used for preparation of homogenates and measurements of IL-6 and TNF-alpha by Elisa. Serum levels of nitrite were also determined and paw slices used for iNOS immunohistochemistry assays. We showed that diabetic rats presented an amplification of the inflammatory response, as related to non-diabetic rats, what was evident 48 h after the edema-induction. The PTX-treatment of diabetic rats reduced glycemia (as related to untreated-diabetic ones) and the paw edema. It also brought edema volumes to values similar to those of non-diabetic rats, at the same observation time. The increased TNF-alpha and IL-6 levels in paws of untreated-diabetic rats were reduced in diabetic animals after PTX treatments. Besides, the increased levels of nitrite in the serum of diabetic rats were also decreased by PTX. Furthermore, a higher number of iNOS immunostained cells was demonstrated in paw tissues from untreated-diabetic rats, as related to those of PTX-treated diabetic animals. Our results show that PTX reduces inflammatory parameters, as pro-inflammatory cytokines and iNOS expression, indicating the potential benefit of the drug for the treatment of diabetes and related pathologic conditions.