Hesperidin protects against stress induced gastric ulcer through regulation of peroxisome proliferator activator receptor gamma in diabetic rats

Abstract Stress induced gastric ulcer is a serious health problem in diabetic patients. Some studies reported that hesperidin (HDN), a citrus bioflavonoid, can bind to and stimulate peroxisome proliferator-activator receptor-gamma (PPAR-γ) which may mediate its antidiabetic, anti-inflammatory and anti-oxidant effects. This work aims to study the possible protective effect of HDN against stress induced gastric ulcer in diabetic rats as well as the possible involvement of PPARγ in this effect. Type 2 diabetes was induced using streptozotocin and nicotinamide. Diabetic rats received either HDN (100 mg/kg/day, orally) & omeprazole (20 mg/kg/day, orally) or HDN (100 mg/kg/day, orally) + GW9662, PPARγ antagonist, (1 mg/kg/day, i.p.) for 8 weeks then acute gastric injury was induced by cold restraint stress technique. Glycemic controls and gastroprotective effects were evaluated by measuring serum levels of glucose and insulin, gastric free and total acidity and gastric ulcer indices. Histopathological examination of gastric mucosa was also performed. To determine the underlying mechanism of action, gastric mucosal expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO-1), cluster of differentiation 45 (CD45), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB) and inducible nitric oxide synthase (iNOS), gastric contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and nitric oxide (NO); as well as superoxide dismutase (SOD) and catalase activities were measured. HDN significantly improved glycemic level; it also reduced gastric acidity and gastric ulcer index and histopathological changes comparable to that produced by omeprazole. Moreover, HDN reduced lipid peroxidation and inflammatory markers levels and enhanced antioxidant capacity. The use of GW9662 significantly abrogated the gastric protective effect of HDN as well as reduced the antioxidant and anti-inflammatory effects. Our work showed, for the first time that, HDN has promising protective effect against stress induced gastric ulcer in diabetic rats through activation of PPARγ.