Curative effect of selenium against indomethacin-induced gastric ulcers in rats

Indomethacin is a nonsteroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the effect of selenium on gastric mucosal lesions in rats. To confirm the curative effect of selenium against indomethacin-induced gastric ulcers, gastric ulcers were induced by oral administration of 25 mg/kg indomethacin, and then different doses (10, 50, and 100 microgram/kg of body weight) of selenium or vehicle were treated by oral gavage for 3 days. Oral administration of indomethacin clearly increased the gastric ulcer area in the stomach, whereas selenium applied for 3 days significantly decreased the gastric ulcer area in a dose-dependent manner. In addition, selenium markedly reduced the increase of lipid peroxidation induced by indomethacin in the gastric mucosa and increased activities of radical scavenging enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in a dose-dependent manner. These results reveal that selenium can heal indomethacininduced gastric ulcers through elimination of the lipid peroxides and activation of radical scavenging enzymes.     

Biphasic activity of resveratrol on indomethacin-induced gastric ulcers

Resveratrol showed biphasic activity in indomethacin-induced gastric ulcerated mice. A protective effect at a lower dose (2 mg kg⁻¹) and a contraindicative effect at a higher dose of Resveratrol (10 mg kg⁻¹) were observed. This phenomenon was possibly controlled by a COX-1 and eNOS balance, which ultimately maintained angiogenesis in Resveratrol-treated pre-ulcerated mice. The lower dose of Resveratrol (2 mg kg⁻¹) augmented eNOS expression without altering COX-1 expression, but, at a higher dose (10 mg kg⁻¹), Resveratrol predominantly suppressed COX-1 expression, which significantly reduced both PGE₂ synthesis and angiogenesis. Thus it ultimately resulted in delay healing of indomethacin-induced gastric ulcers. Hence, it could be concluded that COX-1 and eNOS acted as key regulatory factors switching the biphasic effects of Resveratrol in indomethacin-induced ulcerated mice.     

Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin

Liver injury was induced in female rats using tamoxifen (TAM). Grape seeds (Vitis vinifera) extract (GSE), black seed (Nigella sativa) extract (NSE), curcumin (CUR) or silymarin (SYL) were orally administered to TAM-intoxicated rats. Liver histopathology of TAM-intoxicated:rats showed pathological changes. TAM-intoxication elicited declines in liver antioxidant enzymes levels (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase), reduced glutathione (GSH) and GSH/GSSG ratio plus the hepatic elevations in lipid peroxides, oxidized glutathione (GSSG), tumor necrosis factor-alpha (TNF-alpha) and serum liver enzymes; alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase levels. Oral intake of NSE, GSE, CUR or SYL to TAM-intoxicated rats, attenuated histopathological changes and corrected all parameters mentioned above. Improvements were prominent in case of NSE (similarly SYL) > CUR > GSE. Data indicated that NSE, GSE or CUR act as free radicals scavengers and protect TAM-induced liver injury in rats.     

Gastro-protective effect of methanol extract of Ficus asperifolia bark on indomethacin-induced gastric ulcer in rats

The gastro-protective and antioxidant effects of methanol extract of Ficus asperifolia bark on indomethacin induced gastric ulcer were investigated in male rats. Thirty two male rats divided into 4 equal groups and were treated as follows: group1 (control), 0.5ml of 5% tween 80 (vehicle for the extract), groups 2 and 3, 100 and 500mg/kg of Ficus asperifolia extract respectively and group 4, cimetidine (100mg/kg). After two weeks of daily oral administration of vehicle, extract or cimetidine, gastric ulcer was induced in all rats with indomethacin (40 mg/kg, p.o). Gastric juice pH, gastric acid concentration, gastric ulcer score, percentage gastric ulcer inhibition, activity levels of superoxide dismutase (SOD), catalase and malondiadehyde (MDA) were determined. Ficus asperifolia extract significantly increased gastric pH (p.     

Mechanical assessment of effects of grape seed proanthocyanidins extract on tibial bone diaphysis in rats

We studied the effects of grape seed proanthocyanidins extract (GSPE) given as a ratio of 3 mg in 100 g in a standard diet, on the tibial bone diaphysis in low-calcium fed rats. Measurements of bone density, mineral content, geometry, and bone strength using peripheral quantitative computed tomography (pQCT). Further, the whole tibia bones were tested for mechanical resistance using a material-testing machine, and mineral elements were also determined. Forty male Wistar rats, 5 weeks old, were divided into control (Co), low-calcium diet (LC), low-calcium diet . standard diet (LCS), and low-calcium diet . standard diet with supplementary GSPE (LCSG) groups. We found no significant differences in body weight among the 4 groups, whereas all of the bone parameters in LC were significantly lower than those in Co (p<0.01, except in periosteal perimeter (Peri) p<0.05). The cortical bone mineral content (CtBMC), cortical bone density (CtvBMD) and Peri in LCSG were significantly higher than those in LCS (p<0.01; p<0.01; p<0.05, respectively). All bone parameters in LCSG were significantly higher than those in LC (p<0.01, except in Peri, and stress strain index to reference axis x (xSSI) p<0.05)). In addition, Ca, P, and Zn contents in LCSG were significantly higher than those in LCS (p<0.01; p<0.01; p<0.05, respectively). Our results suggest that GSPE included in a diet mixture with calcium has a beneficial effect on bone formation and bone strength for the treatment of bone debility caused by a low level of calcium.     

The healing effects of Centella extract and asiaticoside on acetic acid induced gastric ulcers in rats

In this study, the healing effects of Centella asiatica water extract (CE) and asiaticoside (AC), an active constituent of CE, on acetic acid induced gastric ulcers (kissing ulcers) in rats were examined. CE was prepared from Centella asiatica dry plant and the concentration of AC in CE was quantitatively determined with the use of high performance liquid chromatography analysis. Different concentrations of CE and AC were orally administered to rats with kissing ulcers. They were found to reduce the size of the ulcers at day 3 and 7 in a dose-dependent manner, with a concomitant attenuation of myeloperoxidase activity at the ulcer tissues. Epithelial cell proliferation and angiogenesis were on the other hand promoted. The expression of basic fibroblast growth factor, an important angiogenic factor, was also upregulated in the ulcer tissues in rats treated with CE or AC. These results further suggest the potential use of Centella asiatica and its active ingredient as anti-gastric ulcers drugs.     

Long-term effects of chromium,grape seed extract,and zinc on various metabolic parameters of rats

Progressive insulin resistance may contribute to both enhanced glycosylation of proteins and nucleic acids and augmented free radical damage commonly associated with aging. Accordingly, ingestion of chromium and antioxidants which improve insulin sensitivity and/or lessen free radical formation could theoretically ameliorate these basic disorders and lessen signs and symptoms of chronic age-related disorders. However, this supposition is based primarily upon acute rather than chronic data. Therefore, we divided 104 F344/BN rats into 2 groups: a control group receiving a basic diet and a test group receiving the same diet with added chromium polynicotinate (5 ppm), zinc monomethionine (18 ppm elemental zinc), and a grape seed extract high in flavonoids (250 ppm). Initial mean systolic blood pressures (SBP) of both control and test groups were 122 mm Hg. Over the first 7 months, the SBP of the control animals steadily increased to 140 mm Hg and remained at this level for the next 7–8 months. In contrast, the SBP of the test animals initially decreased over the first 4 months to as low as 110–114 mm Hg. The SBP then increased over the following months, essentially reaching the starting value of 120 mm Hg. This was still significantly lower than control (p < 0.001). In 12 control and 12 test rats, hepatic TBARS formation, an estimate of lipid peroxidation/free radical formation, was significantly lower after 1 year ingesting the test diet (p < 0.04); and HbA1C was also statistically significantly lower in the test group (5.4 vs. 4.8%, p < 0.003). Circulating levels of cholesterol, HDL, and triglycerides were similar between the two groups. Body, kidney, and liver weights were not different after 1 year ingesting the different diets; but epididymal fat pad weight was less in the group receiving supplements. We conclude that after prolonged supplementation a combination of agents known to sensitize insulin response and act as antioxidants (chromium polynicotinate, grape seed extract, and zinc monomethionine) can markedly lower SBP in normotensive rats, lessen oxidative damage to fats as suggested by decreased TBARS formation, and lower HbA1C without showing signs of toxicity.     

Effects of grape seed proanthocyanidins extract on rat mandibular condyle

We investigated the effects of grape seed proanthocyanidins extract (GSPE) on bone formation by examining total and cortical bone mass, density, architecture, and strength non-invasively using mandibular condyles of Ca-restricted rats. Forty Wistar male rats, each 5 weeks old, were divided into control (C), low-Ca diet (LCaD), low-Ca diet-standard diet (LcaD x SD), and low-Ca diet x Estandard diet with supplementary GSPE (LcaD x SD+GSPE) groups. In LCaD x SD group, after the bone debility was induced by low-Ca diet, a standard diet therapy was given. In LCaD x SD+GSPE group, after the bone debility was induced by low-Ca diet, a standard diet therapy with supplementary GSPE was given. Each mandibular condyle was examined using peripheral quantitative computed tomography (pQCT). There were no significant inter-group differences in body weight seen throughout the experimental period. In LcaD x SD+GSPE, cortical bone cross-sectional area and mineral content were not significantly different from C, while bone mineral content was significantly higher in LcaD x SD+GSPE than in LcaD x SD. Cortical bone density of LcaD x SD+GSPE was not significantly different from that of C, however, that value in LCaD and LcaD x SD was significantly lower than that. The cross-sectional (bending) moment of inertia values in LcaD x SD+GSPE were the highest among all groups, though they did not differ significantly from those in C. Further, the cross-sectional (bending) Stress/Strain Index (SSI) values in LcaD x SD+GSPE were statistically similar to those in C, however, not significant higher than in LcaD x SD. These results suggest that GSPE treatment would increase both bone mass and bone strength on the rat mandibular condyles.     

Evaluation of Pongamia pinnata root extract on gastric ulcers and mucosal offensive and defensive factors in rats

Effect of methanolic extract of P. Pinnata roots (PPRM) was studied against various experimental gastric ulcer models and offensive and defensive gastric mucosal factors in rats. An initial dose-response study using 12.5-50 mg/kg P. Pinnata root extract, when given orally in two divided dose for 4 days + 5th full dose on the day of experiment 60 min before the experiment, indicated 25 mg/kg as an optimal regimen and was used for further study. PPRM showed significant protection against aspirin and 4 hr PL, but not against ethanol-induced gastric ulceration. It showed tendency to decrease acetic acid-induced ulcer after 10 days treatment. Ulcer protective effect of PPRM was due to augmentation of mucosal defensive factors like mucin secretion, life span of mucosal cells, mucosal cell glycoproteins, cell proliferation and prevention of lipid per oxidation rather than on the offensive acid-pepsin secretion.     

Modulation of indomethacin-induced gastric injury by spermine and taurine in rats

This study investigated the involvement of neutrophil infiltration, nitric oxide (NO) generation, and oxidative stress in indomethacin-induced ulcer and the possible gastroprotective potentials of spermine and taurine, known for their tissue regenerating and antioxidant effects, respectively. Male Wistar albino rats (180-220 g) were allocated into a normal control group, ulcer control group (received a single dose of indomethacin 40 mg-kg p.o.), and two ulcer groups pretreated with spermine (150 mg-kg p.o. 1 h before ulcer induction) and taurine (250 mg-kg i.p. for three consecutive days before ulcer induction). The animals were killed 6 h after indomethacin administration, and the gastric juice, serum, and mucosal tissue were used for gastric injury evaluation. Both modulators significantly ameliorated the indomethacin-induced gastric lesions in glandular mucosa. Notably, spermine exhibited the most pronounced effect as manifested by great reduction in the gastric ulcer index, normalization of the elevated gastric acidity, and triggering of mucin production. Spermine and taurine were able to decrease the elevated levels of gastric myeloperoxidase, conjugated diene, and serum NO. However, the lowered tissue NO content was markedly elevated only by taurine. The antioxidant action of taurine was illustrated by restoration of the depressed content of glutathione, normalization of the inhibited activities of glutathione reductase, and superoxide dismutase. These results suggest that spermine and taurine confer significant gastroprotection against indomethacin-induced gastric injury with the priority of spermine.     

Nitroxides prevent exacerbation of indomethacin-induced gastric damage in adjuvant arthritis rats

Nonsteroidal anti-inflammatory drugs are the drugs of choice in the treatment of rheumatoid arthritis (RA) because of their rapid analgesic effect. However, they induce severe gastric damage in RA patients and animals by a process mediated by reactive oxygen species (ROS). Nitroxides (nitroxyl radicals) are widely used as imaging agents and antioxidants to explore the role of ROS generation in the pathogenesis of disease. In this study, the effectiveness of the newly synthesized nitroxides 8-aza-7,7,9,9-tetramethyl-1,4-dioxaspiro[4.5]undecan-8-oxyl (compound 1) and 4-oxo-2,2,6,6-tetraethylpiperidine-1-oxyl (compound 2) in the prevention of gastric ulcers in adjuvant arthritis rats treated with indomethacin was evaluated by monitoring the reaction of reactive oxygen species in gastric tissue with Overhauser-enhanced magnetic resonance imaging (OMRI). Pretreatment with all tested nitroxides suppressed the ulcers induced by indomethacin treatment in arthritic rats. OMRI using compounds 1 and 2 as well as 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) demonstrated a redox imbalance in the stomach of these rats. Lipid peroxide and interleukin (IL)-1β levels in the gastric mucosa were significantly suppressed by compound 1 and TEMPOL, whereas CINC/gro, a member of the IL-8 family, was significantly suppressed by compound 1 only. These results suggest that the preventive effects of nitroxides on gastric ulcers may operate by different mechanisms.     

The protective action of melatonin on indomethacin-induced gastric and testicular oxidative stress in rats

Reactive oxygen species and lipid peroxidation play a role in the pathogenesis induced by the non-steroidal anti-inflammatory drug indomethacin. Melatonin (MLT) protection against indomethacin-induced oxidative tissue injury was investigated in gastric mucosa and testis of rats. MLT was administered intragastrically (i.g.) 30 min before the administration to fasted rats of 20 mg indomethacin/kg rat given i.g.. The area of gastric lesion as well as thiobarbituric acid reactive substances (TBARS) and lactate dehydrogenase (LDH) activity were found to be significantly increased 4 h after administration of indomethacin in rat gastric mucosa and testis indicating acute oxidative injury. MLT pretreatment reduced gastric lesion area to 80% of the indomethacin-treated rats and reduced the rise in TBARS concentration. MLT treatment reduced the LDH activity increase in testis but not in gastric mucosa. In indomethacin-treated rats, both the cytosolic Cu,Zn superoxide dismutase (Cu,Zn-SOD) and mitochondrial Mn-SOD activities were significantly diminished in gastric mucosa as well as the total SOD activity in testis. In addition, glutathione (GSH) content in both tissues was markedly decreased following indomethacin treatment. Pretreatment with MLT significantly ameliorated both the inhibition of SOD activity and the decreased GSH content in both tissues. Thus, these results show the effective antiperoxidative and preventive actions of MLT against indomethacin-induced gastric mucosal damage and testicular oxidative injury and we propose that this action might be relevant for its use with other free radical generating drugs.     

The indomethacin-induced gastric mucosal damage in rats. Effect of gastric acid,acid inhibition,capsaicin-type agents and prostacyclin

In pylorus-ligated rats subcutaneous (sc) pentagastrin (325.5 nmol/kg) or histamine (54.3 μmol/kg), but not the cholinergic linergic agent bethanechol (7.6 or 15.2 μmol/kg), increased gastric mucosal injury by sc indomethacin (55.8 μmol/kg). Intragastric (ig) administration of 0.15 or 0.3 N HCl greatly potentiated injury by sc indomethacin with widespread ulceration, intragastric bleeding and even perforation. The gastric mucosal damage produced by indomethacin plus 0.3 N HCl was reduced by ig capsaicin (3.1–25.1 μM), ig resiniferatoxin (0.38-6.1 μM), by sc atropine (0.15-1.2 μmol/kg) and to a lesser extent by ig prostacyclin (40–267 μM) or sc cimetidine (198.2 μmol/kg). The protective effect of capsaicin or resiniferatoxin was not prevented by atropine or cimetidine treatment. Capsaicin (6.5 mM) enhanced gastric injury by sc or ig indomethacin. Results indicate the importance of early vascular events in the pathogenesis of mucosal injury induced by indomethacin in the stomach and suggest a role for gastric acid in potentiation of such injury. Results further strengthen the idea of a protective role for capsaicin-sensitive sensory nerves in the stomach.     

Effect of low molecular grape seed proanthocyanidins on blood pressure and lipid homeostasis in cafeteria diet-fed rats

Cardiovascular disease (CVD) and related pathologies are the leading cause of death worldwide. Fruits and vegetables are known to improve CVD, an effect that has been associated with flavonoid intake. The aim of this study was to simultaneously evaluate the acute effect of a low molecular grape seed proanthocyanidin extract (LM-GSPE) on two of the main risk factors of CVD, high blood pressure (BP) and dyslipidaemia, using high-fat diet-fed rats. Therefore, male Wistar rats that were cafeteria diet fed for 10 weeks were administered with 375 mg/kg of body weight of LM-GSPE, and the BP as well as plasmatic and hepatic parameters were determined at 6 h post-administration. The BP and plasmatic and hepatic lipid were decreased 6 h after the LM-GSPE administration. Moreover, the liver lipid peroxidation products decreased after the LM-GSPE treatment, indicating a reduction in oxidative stress. However, hepatic-reduced glutathione or plasma angiotensin converting enzyme activity was not altered by the LM-GSPE. In conclusion, grape proanthocyanidins is able to simultaneously reduce more than one risk factor for CVD by decreasing the BP and improving hypertriglyceridaemia at least in part due to an improvement in oxidative stress. These results open up the possibility of using grape proanthocyanidins in functional foods for CVD improvement.     

Monthly variations in drug-induced gastric ulcers in rats

Clinical evidence suggests that there may be some relationship between the occurrence of peptic ulcers and the season of the year. As little experimental work has been carried out on this subject, three drugs commonly used to induce experimental ulcers in rats (acetylsalicylic acid, 300 mg/kg; phenylbutazone, 200 mg/kg; reserpine, 10 mg/kg) were tested every month for one year under standardised experimental conditions (T_a, RH, LD 12:12). In rats given phenylbutazone the maximum area of ulceration was found in October and December, and in rats given acetylsalicylic acid in February and March. In rats given reserpine, there were no significant monthly variations. An influence of climatic factors on ulcer induction cannot be completely excluded. Endogenous conditions might also account for the monthly differences in ulceration.     

Feeding grape seed extract to horses: effects on health, intake and digestion

A feeding trial involving four Thoroughbred race horses was undertaken to establish whether inclusion of grape seed extract (GSE) in the diet of horses undergoing mild exercise had any effects on their general health, intake and digestion. Supplementation with GSE had no effect on either feed or water intake of the horses and the supplement was readily palatable to the horses at all levels of inclusion. Feeding GSE caused no adverse effects in terms of animal health (temperature, pulse and respirations rates), and there were some positive effects related to a presumed alteration in fermentation in the hindgut. Feeding GSE increased faecal pH, changing from acid faeces (pH 6.6) when no GSE was fed to neutral faeces (pH 7.0) when 150 mg GSE/kg body weight (BW) was fed. In addition, blood glucose concentrations were significantly (P < 0.05) decreased when GSE was fed at 100 and 150 mg/kg BW (5.50 ± 0.26 and 5.32 ± 0.72 mmol/l, respectively) compared with the control diet (5.77 ± 0.31 mmol/l). The actual mechanisms causing these alterations are yet to be elucidated, but could have important implications for the prevention of acidosis.     

Experimentally induced ulcers and gastric sensory-motor function in rats

Prior studies have demonstrated that inflammation can sensitize visceral afferent neurons, contributing to the development of hyperalgesia. We hypothesized that both afferent and efferent pathways are affected, resulting in changes in motor and sensory function. Kissing ulcers (KU) were induced in the distal stomach by injecting 60% acetic acid for 45 s into a clamped area of the stomach. In controls, saline was injected into the stomach. A balloon catheter was surgically placed into the stomach, and electromyographic responses to gastric distension were recorded from the acromiotrapezius muscle at various times after ulcer induction. The accommodation reflex was assessed by slowly infusing saline into the distally occluded stomach. Gastric pressure changes in response to vagal stimulation were measured in anesthetized rats. Contractile function of circular muscle strips was examined in vitro using force-displacement transducers. KU caused gastric hypersensitivity that persisted for at least 14 days. Fluid distension of the stomach led to a rapid pressure increase in KU but not in control animals, consistent with an impaired accommodation reflex. Gastric ulcers enhanced the contractile response to vagal stimulation, whereas the effect of cholinergic stimulation on smooth muscle in vitro was not changed. These data suggest that inflammation directly alters gastric sensory and motor function. Increased activation of afferents will trigger vagovagal reflexes, thereby further changing motility and indirectly activating sensory neurons. Thus afferent and efferent pathways both contribute to the development of dyspeptic symptoms.