Protective Effects of Ginger against Aspirin-Induced Gastric Ulcers in ....pdf
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1、11 Yonago Acta medica 2011;54:1119 Abbreviations: IL, interleukin; iNOS, inducible form of NOS; LPS, lipopolysaccharide; NIH, National Institute of Health; NOS, NO synthase; NSAID, nonsteroidal anti-inflammatory drug; PGE2, prostaglandin E2; TNF, tumor necrosis factor Protective Effects of Ginger ag
2、ainst Aspirin-Induced Gastric Ulcers in Rats Zhongzhi Wang, Junichi Hasegawa, Xinhui Wang, Akiko Matsuda, Takahiro Tokuda, Norimasa Miura and Tatsuo Watanabe* Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, and *Division of Integrative Physiology, Departme
3、nt of Functional, Morphological and Regulatory Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan We investigated the mechanism underlying the protective effects of ginger against gastric damage induced by aspirin in rats. Gastric mucosal lesions were produce
4、d by orally ad- ministering 200 mg/kg aspirin suspended in 1% carboxymethylcellulose solution to pylo- ric-ligated male Wistar rats. Ginger powder (200 mg/kg) markedly reduced the aspirin- induced gastric hemorrhagic ulcer area. The total acidity of gastric juice was not signifi- cantly influenced b
5、y aspirin or ginger. Ginger powder did not affect the aspirin-induced reduction in mucosal prostaglandin E2 (PGE2) content; however, it did ameliorate the aspirin-induced increases in mucosal activity of the inducible form of NO synthase (iNOS) and plasma tumor necrosis factor (TNF)- and interleukin
6、 (IL)-1 levels. In the next ex- periment, high and low doses of 6-gingerol and 6-shogaol were used instead of ginger pow- der in the same experimental model to examine their roles in the anti-ulcer mechanism of ginger. Both 6-gingerol and 6-shogaol reduced aspirin induced ulcer formation, mucosal iN
7、OS and plasma TNF- and IL-1 levels. In conclusion, ginger powder prevents the as- pirin induced gastric ulcer formation by reducing mucosal iNOS activity and the plasma levels of inflammatory cytokines but does not affect gastric juice or acid production or mu- cosal PGE2 content. This protective ef
8、fect of ginger powder against gastric ulcers may be attributable to both gingerol and shogaol. Key words: aspirin; gastric damage; ginger powder; inflammatory cytokine; inducible form of NO synthase activity Aspirin is a potent nonsteroidal anti-inflammatory drug (NSAID) that is used for the treatme
9、nt of rheumatoid arthritis and related diseases as well as the prevention of cardiovascular thrombotic diseas- es. Gastric ulcer associated with the use of aspirin is a major problem. Many factors such as gastric acid and pepsin secretion, gastric microcircula- tion, prostaglandin E2 (PGE2) content
10、(Laine et al., 2008), and proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)- (Santucci et al., 1995; Appleyard et al., 1996) play important roles in the genesis of gastric mucosal damage, and its subsequent development (Wang et al., 2007; Wallace, 2008). It has been report
11、ed that increases in NO synthase (NOS) activity is involved in the gastrointestinal mucosal defense and also in the pathogenesis of mucosal damage (Muskara et al., 1999; Wallace et al., 2000). Ginger (Zingiber officinale) has been used as a spice and an ingredient of Chinese traditional 12 Z. Wang e
12、t al. stomach medicine for thousands of years. In tra- ditional medicine, ginger has been used to treat many inflammatory conditions and associated pain (Altman and Marcussen, 2001). The major pungent constituents of ginger, 6-gingerol and 6-shogaol, have been shown to have many interesting phar- ma
13、cological effects, such as anti-oxidant, anti- tumor promoting and anti-inflammatory effects (Surh, 2002; Kim et al., 2005; Young et al., 2005). However, the mechanism underlying the protective effects of ginger against gastric damage is unclear. Here, we investigated the antiulcer effects of ginger
14、 in aspirin-induced gastric ulcer model rats. Materials and Methods Animal experiment using ginger powder The experimental protocol was approved by the ethics committee on animal experiments in Tottori University, and the experiments were carried out in accordance with the guidelines for animal expe
15、ri- ments in the same facility. Male Wistar rats at 8 weeks of age (weigh- ing 300350 g) were purchased from Shimizu Laboratory Supplies (Kyoto, Japan). They were acclimated in an air-conditioned room at 25C and 55% humidity and given standard chaw for a few days. Before surgery, the rats were faste
16、d for 24 h and allowed free access to drinking water. Then, the animals were anesthetized using pentobarbi- tal (30 mg/kg body weight, intraperitoneally), the abdomen was opened, and the pyloric end of stom- ach was ligated without causing any damage to its blood supply. The stomach was then replace
17、d, and the abdominal wall was closed in two layers with sutures. After they had fully recovered from the anes- thesia, the animals were divided into 4 groups of five animals each. Group 1 orally received 3 mL of 1% carboxymethylcellulose in water (vehicle) by gavage. Group 2 orally received ginger p
18、owder (200 mg/kg body weight) suspended in 3 mL of 1% carboxymethylcellulose in water. Group 3 orally received aspirin (200 mg/kg body weight) suspend- ed in 3 mL of 1% carboxymethylcellulose in water. Group 4 orally received aspirin together with gin- ger powder suspended in 3 mL of 1% carboxym- et
19、hylcellulose in water. At 4 h after the test drug administration, the animals were anesthetized, and then blood was collected from the heart, and the stomach was removed after the esophageal end had been tied (Jainu and Devi, 2006; Jainu et al., 2006). The stomach was cut open along the greater curv
20、a- ture, and the contents were collected in tubes and centrifuged at 200 g for 10 min. The resultant supernatant was used for the estimation of acid and gastric juice output. The stomach was then washed with warm saline, and the inner surface was photo- graphed to allow the measurement of the area c
21、ov- ered by hemorrhagic ulceration. Next, the gastric mucosal tissues were removed, frozen in liquid ni- trogen and stored at 80C. The total acid content of the gastric juice was determined by titrating it with 0.01 N NaOH, using phenolphthalein as indi- cator, and was expressed as mEq/4 h/100 g (Ja
22、inu et al., 2006; Wang et al., 2007). The acidity of gas- tric juice was calculated as total acid content/gastric juice volume in mEq/mL (Khushtar et al., 2009). In animal experiments using 6-gingerol and 6-shogaol, the same procedures as were used in the first experiment to produce the pylorus liga
23、ted rats were repeated using high dose (2 mg/kg) and low dose (1 mg/kg) 6-gingerol, and high dose (1 mg/kg) and low dose (0.5 mg/kg) 6-shogaol, in- stead of ginger powder suspended in 3 mL of 1% carboxymethylcellulose in water. The doses of 6-gingerol and 6-shogaol used in the experiment were determ
24、ined by those found in normal ginger (Schwertner and Rios, 2007). Quantification of the gastric hemorrhagic ulcer area using NIH image The photographs of the stomach were digitized and converted to binary images through gray scale im- aging (Khan, 2004). Using the National Institute of Health (NIH)
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