الفهرس 
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Abstract
Gastric ulcer is a worldwide disease, it occurs when aggressive and inflammatory mediators overcome the protective factors. Indomethacin is the NSAID of choice for this type of studies due to its strong ulcerogenic effect. It causes gastric ulcer by inhibition of COX enzymes involved in the production of PGs which produce a gastroprotective effect not only via decreasing acid secretion, but also by increasing the gastric mucus level. Moreover, indomethacin disrupted oxidant/antioxidant balance and elicited both local and vascular mechanisms that promoted extensive damage in the gastric mucosa. Therefore, this model is also well-accepted as oxidative stress-induced gastric disease, since the ulcers might be modulated by oxidative stress. Endogenous CO is a potent cytoprotective agent. It is well-known to have a gastroprotective action through its anti-inflammatory, anti-apoptotic, and vasodilator effects which are mediated by many different mechanisms such as activation of sGC/cGMP pathway, interaction with heme-containing proteins like cytochrome P-450, NADPH oxidase, iNOS, COX-1 and COX- 2, and activation of p38MAPK signaling pathway. Accordingly, the current study was conducted to evaluate the potential gastroprotective effects of CORM2 and its nanoparticles in indomethacininduced gastric ulcer in rats. To fulfill these targets, 64 rats were randomly distributed into 8 groups (n= 8) as follow: normal control group, CORM2 (15 mg/kg, I.P.), gastric ulcer group, gastric ulcer + rantidine (30 mg/kg, I.P.), gastric ulcer + CORM2 (5 mg/kg, I.P), gastric ulcer + CORM2 (10 mg/kg, I.P.), gastric ulcer + (15 mg/kg, I.P.), gastric ulcer + CORM-2 nanoparticles (5 mg/kg, I.P.). Induction of ulcer was achieved by a single oral dose of indomethacin (100 mg/kg). CORM2, CORM2 NPs and rantidine were given daily for 7 days, and in day 7 indomethacin was administered 1 hr following the last dose of each drug. 4 hrs after indomethacin administration, whole blood samples were collected in heparinized tubes to determine COHb percentage. Gastric juice was collected and stomachs were excised and opened from the greater curvature, then rinsed with normal saline and divided into 2 portions. The first portion was fixed in 10% neutral buffered formalin and used for histopathological examination and immunohistochemical staining of COX-1 and COX-2. The second portion was divided into weighted pieces and kept at -80°C for measurement of the following parameters: Lipid peroxides content (measured as MDA). NO content. Nrf2 expression. HO-1 content. Ulcer induction by indomethacin (100 mg/kg) showed the following effects compared with normal control group: Lesions in gastric mucosa. Significant decrease in gastric pH. Significant increase in gastric ulcer score. Significant increase in MDA content. Significant increase in NO content. Significant decrease in HO-1 content. Significant decrease in Nrf2 content. Significant increase in COHb percentage. The histopathological examination of indomethacin group showed ulceration, loss of gastric mucosa and congestion. Immunohistochemical staining of COX-1 showed weak COX-1 expression in less than 10% of gastric mucosal glands with a moderate intensity. Immunohistochemical staining of COX-2 showed very marked COX- 2 expression in more than 60% of gastric mucosal glands with a strong intensity. Pretreatment with ranitidine, CORM2 different doses (5, 10, and 15 mg/kg) and NPs showed the following effects compared with indomethacin group: Significant increase in gastric pH. Significant decrease in gastric ulcer score. Significant decrease in MDA content. Significant decrease in NO content. Significant increase in HO-1 content. Significant increase in Nrf2 content. Significant decrease in COHb percentage. The histopathological examination of ranitidine pretreated group showed hyperplastic gastric glands with no ulceration surrounded by minimal chronic inflammatory cells. Pretreatment of CORM2 (5 and 10 mg/kg) showed a lower grade of ulceration and inflammation as compared to indomethacin group. The dose of 15 mg/kg relieved ulcer and inflammation at a higher degree than the lower doses. On the other hand, pretreatment with CORM2 NPs (5 mg/kg) showed a normal thickness of gastric mucosa with no ulceration or inflammation. Ranitidine, CORM2 in different doses and NPs groups showed increased COX-1 immunostaining. Ranitidine, CORM2 in different doses and NPs groups showed decreased COX-2 immunostaining. CORM2 showed a dose dependent effect in decreasing the contents of MDA and NO and expression of COX-2. CORM2 showed a dose dependent effect in increasing the contents of HO-1 and Nrf2 and expression of COX-1. Pretreatment with CORM2 NPs showed the following effects compared with CORM2 (5 mg/kg) group: Significant decrease in gastric ulcer score. Significant decrease in MDA content Significant decrease in NO content Significant increase in HO-1 content. Significant increase in Nrf2 content. CORM2 NPs showed significant improvement in histopathological examination. CORM2 NPs group showed increased COX-1 immunostaining [score 9] compared to the CORM2 (5 mg/kg) group [score 6]. CORM2 NPs group showed decreased COX-2 immunostaining [score 2] compared to the CORM2 (5 mg/kg) group [score 6].