geranylgeranylacetone and Stomach-Ulcer

Geranylgeranylacetone (GGA) enhances gastric mucosal protection against nonsteroidal anti-inflammatory drugs by upregulating mucosal heat shock proteins (HSP), but the effects of GGA on the human gastric mucosa have not been well examined. This study was conducted to determine whether a clinical dose of GGA protects the human gastric mucosa from diclofenac (DIC)-induced gastric mucosal injury.. The study group comprised 40 healthy volunteers: 20 subjects were randomly assigned to take either placebo (lactose 1.5 g/day) or GGA (150 mg/day) for 2 weeks (study 1), and 20 subjects were assigned to take DIC (75 mg/day) plus placebo (lactose 1.5 g/day) or DIC (75 mg/day) plus GGA (150 mg/day) for 2 weeks (study 2). In both studies, gastroscopic biopsy specimens were obtained before and after treatment. Mucosal HSP70 expression and DNA damage were analyzed by measuring the levels of HSP70 and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG), respectively.. In study 1, GGA increased the mucosal HSP70 expression without increasing the 8-OHdG production. In study 2, DIC treatment increased the 8-OHdG production, whereas the combination of GGA and DIC enhanced the HSP70 expression and attenuated the increase in 8-OHdG induced by DIC.. The clinical dose of GGA enhanced the gastric mucosal HSP70 expression and inhibited the DIC-induced gastric mucosal damage in humans.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Apoptosis; Biopsy; Diclofenac; Diterpenes; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Gastric Mucosa; Gastroscopy; HSP70 Heat-Shock Proteins; Humans; Male; Stomach Ulcer; Treatment Outcome; Up-Regulation

The role of cytoprotective agents in the treatment of ulcers remains unclear. In the present study we investigated the effect of tetraprenylacetone (TAP), a cytoprotective agent, on healing and recurrence of gastric ulcers infected with Helicobacter pylori and on the mucosal microvascular architecture of healed gastric ulcers.. Ninety-five gastric ulcer patients with H. pylori infection were studied.. Gastric ulcer patients with H. pylori infection received 20 mg omeprazole (44 patients) or 20 mg omeprazole and 150 mg TAP (46 patients) in random fashion. Ulcer healing was assessed with endoscopy 12 weeks after the start of treatment. The patients with healed ulcer were followed up for another 12 months without further therapy. During endoscopic examination at week 12, biopsy specimens were obtained from healed gastric ulcers, and the gastric mucosal microvascular architecture of the biopsy specimens was observed by means of the alkaline phosphatase staining method.. The rate of ulcer healing at week 12 was similar in patients treated with omeprazole with and without TAP. However, at or within 12 months of the start of follow-up observation, ulcers recurred significantly less frequently in patients treated with both omeprazole and TAP than in those treated with omeprazole alone. Alkaline phosphatase staining methods showed that the mucosal microvascular architecture improved significantly more frequently in healed gastric ulcers that had been treated with both omeprazole and TAP than in those treated with omeprazole alone.. Treatment with TAP plus omeprazole significantly decreases ulcer recurrence through TAP's improved mucosal restoration.

Topics: Adult; Aged; Anti-Ulcer Agents; Diterpenes; Drug Therapy, Combination; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Male; Microcirculation; Middle Aged; Omeprazole; Recurrence; Stomach Ulcer; Treatment Outcome; Wound Healing

The aim of this study was to compare the additive effect of rebamipide with that of teprenone in combination with dual therapy on H. pylori eradication. A total of 102 H. pylori-positive gastric ulcer patients were assigned at random to two groups; in addition to dual therapy (amoxicillin 500 mg thrice daily and lansoprazole 30 mg every morning for two weeks), one group received rebamipide 100 mg thrice daily for eight weeks, while the other group received teprenone 50 mg thrice daily for eight weeks. H. pylori diagnosis after treatment was made by [13C]UBT. The ulcer healing rate was 85.7% in the rebamipide group and 79.5% in the teprenone group (P = NS). The eradication rate was 68.4% (95% CI = 54-83%) in the rebamipide group and 47.7% (95% CI = 32-61%) in the teprenone group (P = 0.043) by per-protocol analysis. These findings suggest that the efficacy of dual therapy may be increased by the administration of rebamipide.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Alanine; Amoxicillin; Anti-Ulcer Agents; Diterpenes; Drug Therapy, Combination; Enzyme Inhibitors; Helicobacter Infections; Helicobacter pylori; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Penicillins; Proton Pump Inhibitors; Quinolones; Stomach Ulcer; Treatment Outcome

One hundred and six patients with active gastric ulcer proven by endoscopy were randomly allocated to receive cimetidine 800 mg at bedtime + teprenone 50 mg thrice daily; or cimetidine 800 mg at bedtime alone in a trial comparing the ulcer healing rate and the quality of healing at 4 or 8 weeks. At 4 weeks 72.4% (42/58) of those on cimetidine + teprenone and 52.1% (25/48) on cimetidine alone had ulcers healed in comparison of 93.1% (54/58) and 89.6% (43/48) respectively at 8 weeks. The difference was significant at 4 weeks, indicating the ulcer heal more rapidly in the combination therapy group. The stage S2 achievement rates were 34.5% (20/58) and 10.4% (5/48) at 4 weeks (P < 0.05), 50.0% (29/58) and 20.8% (10/48) at 8 weeks (P < 0.05) respectively, indicating the quality of ulcer healing was much better in the combination therapy group. The gastric mucosal hexosamine levels increase significantly after treatment (17.79 +/- 2.00 micrograms/mg) as compared to that before treatment (14.27 +/- 2.47 micrograms/mg) in the combination therapy group, indicating that teprenone stimulates macromolecular glycoprotein synthesis in gastric mucosa. This is thought to be a significant factor in the healing process of gastric ulceration.. It is reasonable to administer teprenone, an agent increasing mucosal resistance, concurrently with H2 blockers in the treatment of active gastric ulcers.

Topics: Anti-Ulcer Agents; Cimetidine; Diterpenes; Drug Therapy, Combination; Female; Gastric Mucosa; Hexosamines; Histamine H2 Antagonists; Humans; Male; Stomach Ulcer

To establish a rat ethanol gastritis model, we evaluated the effects of ethanol on gastric mucosa and studied the preventive effects of geranylgeranylacetone on ethanol-induced chronic gastritis.. One hundred male Sprague-Dawley rats were randomly divided into 4 equal groups: normal control group, undergoing gastric perfusion of normal saline (NS) by gastrogavage; model control group and 2 model therapy groups that underwent gastric perfusion with ethanol (distillate spirits with 56% ethanol content) by gastrogavage for 4 wk. Low or high doses of geranylgeranylacetone were added 1 h before ethanol perfusion in the 2 model therapy groups, while the same amount of NS, instead of geranylgeranylacetone was used in that model control group. The rats were then sacrificed and stomachs were removed. The injury level of the gastric mucosa was observed by light and electron microscopy, and the levels of prostaglandin 2 (PGE₂), endothelin-1 (ET-1) and nitric oxide (NO) were measured by radioimmunoassay and the Griess method.. The gastric mucosal epidermal damage score (EDS; 4.5) and ulcer index (UI; 12.0) of the model control group were significantly higher than that of the normal control group (0 and 0 respectively, all P = 0.000). The gastric mucosal EDS and UI of the 2 model therapy groups (EDS: 2.5 and 2.0; UI: 3.5 and 3.0) were significantly lower than that of the model control group (all P < 0.01). There was no statistically significant difference between the low-dose and high-dose model therapy groups. The expression value of plasma ET-1 of the model control group was higher than that of the normal control group (P < 0.01) and the 2 model therapy groups (all P < 0.01). The expression values of gastric mucosal PGE₂ and serum NO of the model control group were lower than those of the normal control group (all P < 0.05) and the 2 model therapy groups (all P < 0.05). The thickness of the gastric mucous layerand the hexosamine content in the model control group were significantly lower than that in the normal control group (all P < 0.01) and the 2 model therapy groups (all P < 0.05). Scanning and transmission electron microscopy observation showed that in the model control group, the epithelial junctions were vague, the intercellular joints disappeared and damage of the intracellular organelles were significantly worse than those in the normal control group. However, in the 2 model therapy groups, damage to the intercellular joints and organelles was ameliorate relative to the model control group.. Administration of geranylgeranylacetone was correlated with a more favorable pattern of gastric mucosa damage after ethanol perfusion. The mechanism could be related to regulation of ET-1, NO and PGE₂.

Topics: Animals; Anti-Ulcer Agents; Cytoprotection; Dinoprostone; Disease Models, Animal; Diterpenes; Endothelin-1; Ethanol; Gastric Mucosa; Gastritis; Male; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nitric Oxide; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Stomach Ulcer

It is well known that heat shock proteins (HSPs) are induced by various stressors in order to confer protection against such stressors. Since stressor-induced tissue damage is involved in various diseases, especially gastrointestinal diseases, such as gastric ulcer, it has been thought that HSPs are protective against these diseases. Indirect lines of evidence, such as identification of geranylgeranylacetone (GGA, a leading anti-ulcer drug in Japanese market) as non-toxic HSP-inducer, suggest that HSPs provide a major protective mechanism against irritant-induced gastric lesions. However, no direct evidences that support this notion exits. Furthermore, because GGA has other gastroprotective effects, it was not clear whether HSP-induction by GGA is the main mechanism for its anti-ulcer effect. In this article, I review our recent work on protective roles of HSPs against gastrointestinal diseases, using transgenic mice. We obtained genetic evidence showing not only that HSPs are protective against irritant-induced gastric lesions but also that GGA achieves its anti-ulcer effect through induction of HSPs. We also obtained genetic evidence that HSPs are protective against inflammatory bowel disease (IBD)-related colitis and lesions of small intestine. Furthermore, we found that GGA is effective against these diseases. Based on these observations, we propose that non-toxic HSP-inducers, such as GGA are therapeutically beneficial for these diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Diterpenes; Drug Evaluation, Preclinical; Gastrointestinal Tract; Heat-Shock Proteins; Inflammatory Bowel Diseases; Intestinal Diseases; Intestine, Small; Irritants; Mice; Mice, Transgenic; Protective Agents; Stomach Ulcer

A major clinical problem encountered with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, is gastrointestinal complications. Both NSAID-dependent cyclooxygenase inhibition and gastric mucosal apoptosis are involved in NSAID-produced gastric lesions, and this apoptosis is mediated by the endoplasmic reticulum stress response and resulting activation of Bax. Heat shock proteins (HSPs) have been suggested to protect gastric mucosa from NSAID-induced lesions; here we have tested this idea genetically. The severity of gastric lesions produced by indomethacin was worse in mice lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes, than in control mice. Indomethacin administration up-regulated the expression of gastric mucosal HSP70. Indomethacin-induced gastric lesions were ameliorated in transgenic mice expressing HSP70. After indomethacin administration, fewer apoptotic cells were observed in the gastric mucosa of transgenic mice expressing HSP70 than in wild-type mice, whereas the gastric levels of prostaglandin E(2) for the two were indistinguishable. This suggests that expression of HSP70 ameliorates indomethacin-induced gastric lesions by affecting mucosal apoptosis. Suppression of HSP70 expression in vitro stimulated indomethacin-induced apoptosis and activation of Bax but not the endoplasmic reticulum stress response. Geranylgeranylacetone induced HSP70 at gastric mucosa in an HSF1-dependent manner and suppressed the formation of indomethacin-induced gastric lesions in wild-type mice but not in HSF1-null mice. The results of this study provide direct genetic evidence that expression of HSP70 confers gastric protection against indomethacin-induced lesions by inhibiting the activation of Bax. The HSP inducing activity of geranylgeranylacetone seems to contribute to its gastroprotective activity against indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Dinoprostone; Diterpenes; DNA-Binding Proteins; Flow Cytometry; Gastric Mucosa; Heat Shock Transcription Factors; HSP70 Heat-Shock Proteins; Humans; Immunoblotting; Immunohistochemistry; In Situ Nick-End Labeling; Indomethacin; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Stomach Ulcer; Transcription Factors; Transfection

To estimate the effect of teprenone on the expression of heat shock protein (HSP) 70 and c-fos in stomach following prednisolone ingestion.. Fifty male Sprague-Dawley rats were randomly into 5 equal groups: normal control group, undergoing gastric perfusion of normal saline (NS) for 7 days, and since the 4 th day undergoing fasting for 4 days; model control group, undergoing gastric perfusion of NS for 7 days, and since the 4 th day undergoing fasting and subcutaneous injection of prednisolone 40 mg/kg for 4 days; and 3 model therapy groups, undergoing gastric perfusion with low, middle, and high dose of teprenone (50 mg/kg, 100 mg/kg, and 200 mg/kg respectively) for 7 days and undergoing fasting and subcutaneous injection of prednisolone 40 mg/kg since the 4 th day. Twenty-four hours after the last administration of drugs, the rats were killed with their stomachs taken out. The gastric ulcer index (UI) was measured. HE staining was used to observe the injury index of the gastric mucosa. The mRNA expression of HSP70 in the gastric tissue was semi-quantitatively detected with reverse transcription-polymerase chain reaction. The protein expression of c-fos in the gastric tissue was detected with immunohistochemical staining.. The injury index of the gastric mucosa of the model control group was 5.5, significantly higher than that of the normal control group (0, P = 0.000), and the injury indexes of the 3 teprenone groups were all significantly lower than that of the model control group dose-dependently (all P < 0.01). The UI of the model control group was 44.5, significantly higher than that of the normal control group (0, P = 0.000), and the UI values of the 3 teprenone groups were 32.5, 23.0, and 23.0 respectively, all significantly lower than that of the model control group dose-dependently (all P < 0.01). The expression value of c-fos of the model control group was 42 +/- 8, significantly higher than that of the normal control group (P < 0.01), and that expression values of c-fos of the 3 teprenone groups were all significantly lower than that of the model control groups dose-dependently (all P < 0.01). The expression value of HSP70 mRNA of the model control group was 0.22 +/- 0.03, significantly higher than that of the normal control group (0.04 +/- 0.02, P < 0.01), and the expression values of HSP70 mRNA of the 3 teprenone groups were 0.36 +/- 0.05, 0.41 +/- 0.09, and 0.49 +/- 0.05 respectively, all significantly higher than that of the model control group (all P < 0.01).. Teprenone is Pretreatment with teprenone, beneficial cytoprotective agent of gastric mucosa, has a gastroprotective effect against steroid-induced mucosal damage to a certain extent with the mechanism related to c-fos and HSP70 l level in the gastric mucosa.

Topics: Animals; Diterpenes; Gastric Mucosa; Gene Expression; HSP70 Heat-Shock Proteins; Immunohistochemistry; Male; Prednisolone; Proto-Oncogene Proteins c-fos; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Stomach Ulcer

Gastric lesions result from an imbalance between aggressive and defensive factors. Indirect lines of evidence suggest that heat shock proteins (HSPs) induced by various aggressive factors provide a major protective mechanism. In this study, we compared gastric ulcerogenic response in wild-type mice and in those lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes. The severity of gastric lesions induced by ethanol or hydrochloric acid was worsened in HSF1-null mice. Immunoblotting, real-time reverse transcription-polymerase chain reaction, immunohistochemical analysis, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed that the ethanol administration up-regulated gastric mucosal HSPs, in particular HSP70, in an HSF1-dependent manner, and more apoptotic cells were observed in the gastric mucosa of HSF1-null mice than in wild-type mice. In contrast, other parameters governing the gastric ulcerogenic response, including gastric acid secretion, gastric mucosal blood flow, and prostaglandin E(2) levels, were not significantly affected by the absence of the hsf1 gene. Geranylgeranylacetone (GGA), a clinically used antiulcer drug with HSP-inducing activity, suppressed ethanol-induced gastric lesions in wild-type mice but not in heat shock factor 1 (HSF1)-null mice. The results suggest that the aggravation of irritant-induced gastric lesions in HSF1-null mice is due to their inability to up-regulate HSPs, leading to apoptosis. It is also suggested that the HSP-inducing activity of GGA contributes to the drug's antiulcer activity. This study provides direct genetic evidence that HSPs, after their HSF1-dependent up-regulation, confer gastric protection against the irritant-induced lesions.

Topics: Animals; Apoptosis; Cells, Cultured; Diterpenes; DNA-Binding Proteins; Ethanol; Gastric Mucosa; Heat Shock Transcription Factors; Heat-Shock Proteins; Humans; Hydrochloric Acid; Mice; Mice, Knockout; Stomach Ulcer; Transcription Factors; Up-Regulation

To explore the mucosal protective effect on the quality of gastric ulcer healing.. Gastric ulcers were induced in male rats by serosal application of acetic acid. Rats were gavaged for 14 days with saline, omeprazole (OME), teprenone (TEP) and TEP plus OME starting 3 days after ulcer induction. Then the tissues and blood samples were obtained and measured.. The lower ulcer index (UI) and increased ulcer inhibition rate were observed in OME and OME+TEP groups. In TEP and OME+TEP groups, restored mucosa thickness increased, cystically dilated glands decreased, microvessels in connective tissue increased, the secretion of mucus, hexosamine, PGE(2), bFGF were enhanced, the expression of EGFR was increased.. TEP can improve the quality of gastric ulcer healing, when combined with OME,the effect is more marked.

Topics: Acetic Acid; Animals; Anti-Ulcer Agents; Diterpenes; Drug Therapy, Combination; ErbB Receptors; Gastric Mucosa; Male; Omeprazole; Rats; Rats, Wistar; Secondary Prevention; Stomach Ulcer; Wound Healing

Direct gastric mucosal cell damage mediated by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. We recently suggested that this direct cytotoxicity of NSAIDs is caused by their membrane-permeabilization activity. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, can protect gastric mucosa against lesion formation mediated by NSAIDs. However, the mechanism by which this occurs is not fully understood. In this study, we show that GGA acts to stabilize membranes against NSAIDs. GGA suppressed NSAID-induced permeabilization of calcein-loaded liposomes and NSAID-induced stimulation of K(+)-efflux across the cytoplasmic membrane in cells. GGA was effective even when coadministered with NSAIDs and was also able to restore membrane fluidity that had been compromised by NSAIDs. This mechanism seems to play an important role in the antiulcer activity of GGA.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Cell Membrane Permeability; Diterpenes; Fluorescence Polarization; Gastric Mucosa; Humans; Ion Transport; Membrane Fluidity; Potassium; Stomach Ulcer; Tumor Cells, Cultured

To estimate the effects of teprenone on protecting gastric mucosa against steroids-induced damage.. Fifty male Sprague-Dawley rats were randomly divided into 5 equal groups: normal control group, undergoing gastric infusion of normal saline for 7 days and fasting since the 4 th day for 4 days; model control group, undergoing gastric infusion of normal saline for 7 days and fasting and hypodermal injection of prednisolone 40 mg/kg since the 4 th day for 4 days; low dose teprenone group, undergoing gastric infusion of teprenone 50 mg/kg for 7 days and fasting and hypodermal injection of prednisolone 40 mg/kg since the 4 th day; middle dose teprenone group, undergoing gastric infusion of teprenone 50 mg/kg for 7 days and fasting and hypodermal injection of prednisolone 40 mg/kg since the 4 th day; and high dose teprenone group, undergoing gastric infusion of teprenone 200 mg/kg for 7 days and fasting and hypodermal injection of prednisolone 40 mg/kg since the 4 th day. Samples of gastric mucosa were taken out 24 hours after the last drug administration to calculate the ulcer index and observe the histological changes. Blood samples were collected from the abdominal cardinal vein. The levels of plasma ET-1 and prostaglandin E2 were examined by radioimmunoassay. Serum level of nitric oxide (NO) was determined by Griess method.. In the model control group, the ulcer index, grade of histological lesions and ET-1 level increased significantly compared with the normal control group (44.5 vs. 0, 5.5 vs. 0, and 399 pg/ml +/- 74 pg/ml vs. 279 pg/ml +/- 56 pg/ml, all P < 0.01), the PGE(2) level decreased significantly. (154 pg/mg +/- 83 pg/mg vs 337 pg/mg +/- 112 pg/mg, P < 0.01), and the NO level did not changed significantly. In the 3 teprenone groups, the ulcer index decreased (32.5, 23.0, and 23.0 vs. 44.5, all P < 0.01), grade of histological lesions decreased (3.0, 3.0, and 1.5 vs. 5.5, all P < 0.01), ET-1 level decreased (299 pg/ml +/- 99 pg/ml, 284 pg/ml +/- 85 pg/ml, and 189 pg/ml +/- 32 pg/ml vs. 399 pg/ml +/- 74 pg/ml, P < 0.05, P < 0.01, and P < 0.01), the No level increased (56 micromol/L +/- 16 micromol/L, 62 micromol/L +/- 12 micromol/L, and 83 micromol/L +/- 9 micromol/L vs. 27 micromol/L +/- 5 micromol/L, all P < 0.01), and the PGE(2) level increased (190 pg/mg +/- 58 pg/mg, 196 pg/mg +/- 35 pg/mg, 241 pg/mg +/- 65 pg/mg vs. 154 pg/mg +/- 83 pg/mg, P > 0.05, P > 0.05, and P < 0.05) compared with the model control group.. Teprenone is a beneficial cytoprotective agent of gastric mucosa. Pretreatment with teprenone has gastroprotective effect against steroids-induced mucosal damage to a certain extent with a mechanism related to ET-1, NO, and PGE(2) concentrations in blood or gastric mucosa.

Topics: Animals; Anti-Ulcer Agents; Diterpenes; Gastric Mucosa; Male; Prednisolone; Random Allocation; Rats; Rats, Sprague-Dawley; Stomach Ulcer

The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17-nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion progression was examined in rats with a single intraperitoneal (i.p.) injection of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was orally administered 0.5 h after compound 48/80 treatment at which time gastric mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80-treated rats showed increases in myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreases in Se-glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h after the treatment. Post-administered teprenone attenuated all these changes dose-dependently. These results indicate that teprenone prevents acute gastric mucosal lesion progression in compound 48/80-treated rats possibly by suppressing gastric mucus depletion, neutrophil infiltration and oxidative stress in the gastric mucosal tissue.

Topics: Animals; Anti-Ulcer Agents; Diterpenes; Gastric Mucosa; Glutathione Peroxidase; Hexosamines; Histamine; Male; p-Methoxy-N-methylphenethylamine; Peroxidase; Rats; Regional Blood Flow; Serotonin; Stomach Ulcer; Thiobarbituric Acid Reactive Substances; Vitamin E; Xanthine Oxidase

The cytoprotective effect of heat shock proteins (HSPs) promises new therapeutic modalities for medical treatment. We examined the anti-ulcer effect of cholesteryl glucoside (1-O-cholesteryl-beta-D-glucopyranoside, CG) on cold-restraint stress-induced gastric ulcer in rats, in terms of its correlative ability to activate heat shock factor (HSF) and to induce HSP70. Rapid induction of CG occurred in animal tissues, especially in stomach, after exposure to stress, indicating that this glycolipid might act as an anti-stress, lipid mediator involved in the very early stages of stress-induced signal transduction. Orally administered CG apparently showed anti-ulcer activity in rats via HSF activation and HSP70 induction. When compared with geranylgeranylacetone (GGA), the well known as an effective, synthetic anti-ulcer agent, CG proved to have the same level of strength on ulcer inhibition. GGA caused CG and HSP70 induction in gastric mucosa, indicating that GGA induced HSP70 via CG production. CG thus might be useful for medical treatment of stress-induced diseases, and as an anti-stress supplement for daily diet.

Topics: Animals; Anti-Ulcer Agents; Cholesterol; Diterpenes; Female; HSP70 Heat-Shock Proteins; Molecular Structure; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Stress, Psychological; Temperature

The protective effect of teprenone, an anti-ulcer drug, against acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Teprenone (50, 100, or 200 mg/kg) was orally administered 0.5 h before compound 48/80 treatment. Administered teprenone prevented gastric mucosal lesion development found at 3 h after compound 48/80 treatment dose-dependently, although no dose of teprenone affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. Increases in the activities of myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase and the content of thiobarbituric acid reactive substances (an index of lipid peroxidation) and decreases in the contents of hexosamine (a marker of gastric mucus) and adherent mucus occurred in gastric mucosal tissues at 3 h after compound 48/80 treatment. Administered teprenone dose-dependently attenuated all these changes found at 3 h after compound 48/80 treatment. These results indicate that orally administered teprenone protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its stimulatory action on gastric mucus synthesis and secretion and its inhibitory action on neutrophil infiltration and enhanced lipid peroxidation in the gastric mucosal tissue.

Topics: Acute Disease; Animals; Cell Degranulation; Diterpenes; Dose-Response Relationship, Drug; Gastric Mucosa; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Rats; Rats, Wistar; Stomach Ulcer

Acute gastric mucosal lesions caused by stress or noxious stimuli are important to consider in the management of critically or chronically ill patients. Protein malnutrition has been implicated as a risk factor for stress ulcer and subsequent complications in those patients. When male Wistar rats fed a 5% or 20% casein diet for 3 weeks were exposed to restraint and water-immersion stress, the low-protein diet significantly increased the ulcer index. The low-protein diet did not change the level of heat shock factor 1 (HSF1) in gastric mucosa but it did attenuate the HSF1 activation after exposure to the stress, resulting in the inhibition of HSP70 mRNA expression and HSP70 induction in gastric mucosa. HSP70 is crucial for the maintenance of cell integrity during pathophysiologic conditions; therefore the impaired HSP70 induction appeared to at least in part aggravate stress ulcer. We also tested whether a non-toxic HSP70 inducer, geranyl-geranyl-acetone (GGA), effectively improved the mucosal integrity by stimulating HSP70 induction under protein malnutrition. Intragastric administration of GGA (200 mg/kg twice a day) to the protein-malnourished rats for up to 1 week failed to stimulate the HSP70 induction. However, the administration of GGA (200 mg/kg twice a day) for 3 weeks restored HSP70 induction and induced higher resistance against stress ulcer as compared with results in vehicle-treated, normally nourished rats. Our results suggest that GGA may have a potential benefit for the prevention of stress ulcer in chronically or critically ill patients with protein malnutrition.

Topics: Animals; Anti-Ulcer Agents; Dietary Proteins; Diterpenes; Gastric Mucosa; Heat Stress Disorders; HSP70 Heat-Shock Proteins; Male; Rats; Rats, Wistar; Stomach Ulcer

We designed an animal model in order to clarify whether Helicobacter pylori infection causes the gastric mucosal lesion frequently seen in cirrhotic patients.. Ammonia (NH3) solution was given to rats with carbon tetrachloride-induced cirrhosis. The gastric mucosal hexosamine (Hx) content and histopathological findings in the cirrhotic rats were analysed and compared with those of the intact liver rats. Moreover, the usefulness of geranylgeranylacetone (GGA) was investigated in both rat groups. Both rat groups were subdivided according to the treatment as follows: a control group, an NH3 (0.02% solution) group, and an NH3 + GGA (400 mg/kg per day) group; and fed for 4 weeks.. The gastric mucosal Hx content of the control group of the cirrhotic rats (16.7 +/- 5.2 microg/mg) was significantly lower than that of the control group of the intact liver rats (26.6 +/- 4.5 microg/mg, P < 0.05). In the cirrhotic rats, the Hx content of both the NH3 (31.9 +/- 13.1 microg/mg) and the NH3 + GGA group (31.9 +/- 9.8 microg/mg) was significantly higher than the Hx content of the control group (P < 0.05). Microscopically, in the cirrhotic rats, while scattered mucosal erosions were recognized in three of five rats of the NH3 group, there were no erosions in any rats of the NH3 + GGA group.. These data suggest that the gastric mucosal defence mechanism is defective in liver cirrhosis and that NH3 enhances this defensive mechanism by acting as mild irritant; however, in some cirrhotics this results in gastric erosion due to excessive irritation. Geranylgeranylacetone protects the gastric mucosa against NH3 irritation in cirrhotics without enhancing the Hx content. Thus, H. pylori infection may be a possible cause of the gastric mucosal lesion in patients with liver cirrhosis. The mechanism of the therapeutic effect of GGA is not due to an enhancement of the gastric mucosal Hx content.

Topics: Ammonia; Animals; Anti-Ulcer Agents; Carbon Tetrachloride; Disease Models, Animal; Diterpenes; Gastric Mucosa; Hexosamines; Liver Cirrhosis, Experimental; Male; Rats; Rats, Sprague-Dawley; Stomach Ulcer

c-Kit is a receptor tyrosine kinase, and it is encoded by the mouse W locus. Mutant W/Wv mice develop spontaneous gastric antral ulcers. The aim of the present study was to investigate the pathogenesis of these gastric ulcers and to examine the effects of two antiulcer drugs; a proton pump inhibitor (2{[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methyl-sulfinyl}-1H -benzimidazole sodium salt, rabeprazole) and a mucosal protective drug (geranylgeranylacetone, GGA), on the gastric ulcers. The inhibition of the gastric acid secretion by rabeprazole (30 mg/kg body weight, subcutaneous injection once a day for six weeks) significantly increased the gastric ulcer formation compared to the controls. In contrast, the GGA treatment (100 mg/kg body weight, oral administration for six weeks) significantly inhibited the ulcer formation. Bile reflux was seen in these mutant mice, and they showed no cyclic intense contractions in the gastric antrum. These results suggest that bile reflux due to the disturbance of gastric antral movement is a cause of the spontaneous gastric ulcers in W/Wv mice.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Animals; Anti-Ulcer Agents; Benzimidazoles; Bile Acids and Salts; Bile Reflux; Diterpenes; Drug Evaluation, Preclinical; Gastric Mucosa; Gastrointestinal Motility; Hydrogen-Ion Concentration; Injections, Subcutaneous; Male; Mice; Mice, Mutant Strains; Omeprazole; Proton Pump Inhibitors; Rabeprazole; Stomach; Stomach Ulcer

An antiulcer drug, geranylgeranylacetone (GGA), rapidly induces resistance of gastric mucosal cells to irritants in vivo and in vitro. The aim of this study was to elucidate the mechanism of this action.. Heat shock proteins (HSPs) were detected by immunoblotting with antibody against HSP90, HSP70, heat shock cognate protein 70, or HSP60. HSP70 messenger RNA level was measured by Northern hybridization with an HSP70 complementary DNA probe. Activation of the heat shock factor was detected by gel mobility shift assay with the heat shock element oligonucleotide.. GGA induced resistance of cultured guinea pig gastric mucosal cells against ethanol-induced exfoliation and damage within 30 minutes, proportionally to the induction of the HSPs. This protection was blocked by cycloheximide but not by indomethacin. GGA caused rapid activation of heat shock factor 1 and expression of HSP70 messenger RNA in the cells. Intragastric administration of GGA to rats induced HSPs in gastric mucosa. The administration of GGA additionally enhanced the heat shock response and reduced ulcer formation in rats subjected to restraint and water-immersion stress.. GGA may induce transcriptional activation of HSP genes, and this novel action may increase gastric mucosal defense at conditions of stress.

Topics: Animals; Anti-Ulcer Agents; Base Sequence; Blotting, Northern; Cells, Cultured; Chaperonin 60; Diterpenes; Gastric Mucosa; Guinea Pigs; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Immersion; Male; Molecular Sequence Data; Rats; RNA, Messenger; Stomach Ulcer; Stress, Physiological; Transcriptional Activation

We investigated the development of gastric damage and body weight (BW) loss in lateral hypothalamic area (LHA)-lesioned rats, measured 2 h and 1 and 3 days after the lesioning (experiment 1), as well as the effects of geranylgeranylacetone (GGA), a cytoprotective antiulcer agent, on these disorders (experiment 2). In experiment 1, BW of LHA-lesioned rats decreased throughout the 3-day experiment. In LHA-lesioned rats, gastric mucosal lesions appeared 1 day after lesioning in the glandular portion and persisted, whereas those in the rumenal portion appeared only after 3 days. Gastric transepithelial potential differences (PDs) of glandular portion began to decrease after 2 h and had decreased in both portions. Gastric acid output was increased transiently at 2 h but it was not high after 1 day and after 3 days was lower than that in sham-LHA-lesioned rats. In experiment 2, PDs of the rumenal decreased more in LHA-lesioned rats than in sham-LHA-lesioned rats pair fed to LHA-lesioned rats after 3 days. Three days of treatment with GGA (200 mg/kg ip) improved PDs of rumenal and glandular portions in LHA-lesioned rats and reduced lesions of the rumenal portion. Loss of BW in LHA-lesioned rats was significantly but not completely inhibited by GGA. These results indicate that disturbance to the gastric defensive mechanism plays an important role in the development of gastric lesions after LHA lesions and that the impairment of gastric functions may be a partial cause of the loss of BW in LHA-lesioned rats.

Topics: Animals; Anti-Ulcer Agents; Body Weight; Diterpenes; Feeding Behavior; Female; Gastric Acid; Gastric Mucosa; Hypothalamic Area, Lateral; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Weight Loss

The effects of intragastric administration of teprenone on acute gastric mucosal lesions induced by cold-restraint stress was investigated using a model of obstructive jaundice. Rats received teprenone 200 mg/kg/day for a week before stress; nontreated rats served as controls. Teprenone suppressed stress-induced depressions in defensive factors (blood flow, transmucosal potential difference, hexosamine content and lectin staining of carbohydrate residues) and suppressed increases in lesion-enhancing factors (gastric mucosal lysosomal enzyme activity and thiobarbituric acid reactants showing lipid peroxidation). Intragastric pH did not change significantly with teprenone but the ulcer index decreased. These results showed that teprenone protects gastric mucosa against stress, even in the presence of obstructive jaundice.

Topics: Animals; Anti-Ulcer Agents; Cholestasis; Cold Temperature; Diterpenes; Gastric Mucosa; Male; Rats; Rats, Wistar; Restraint, Physical; Stomach Ulcer; Stress, Physiological

Since gastric mucosal lesions are frequently encountered in patients with liver disease, we measured the levels of gastric mucosal hexosamine. In chronic hepatitis patients, hexosamine levels were reduced in both the antrum and corpus as compared with those in normal controls, while values in the advanced liver cirrhosis group (total bilirubin greater than 5 mg/dl) were lower than in the less advanced group. Although the presence or absence of esophageal varices had no influence on hexosamine, higher concentrations were found in patients with the red color sign (+) in comparison with those with negative red color sign (-). One month after endoscopic injection sclerotherapy of esophageal varices, hexosamine did not change, but decreases were seen in both the antrum and corpus at 3 months. We observed an increase in gastric mucosal blood flow after treatment with teprenone, a new antiulcerative agent, in normal controls. Gastric mucosal hexosamine increased significantly after teprenone treatment in both chronic hepatitis and liver cirrhosis groups. From these results, we conclude that hexosamine has a defensive action against gastric lesions in various liver diseases.

Topics: Anti-Ulcer Agents; Carcinoma, Hepatocellular; Diterpenes; Duodenal Ulcer; Female; Gastric Mucosa; Hexosamines; Humans; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Stomach Ulcer

Effects of KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5-200 mg/kg inhibited water-immersion stress- and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicating that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5-100 mg/kg, also inhibited ethanol-induced gastric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB-5492 was 3 times more potent than teprenone, whereas cimetidine produced no obvious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-induced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti-ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Cimetidine; Diterpenes; Gastric Acid; Gastric Mucosa; Hexosamines; Male; Piperazines; Rats; Rats, Inbred Strains; Stomach Ulcer

The purpose of this study was to clarify the involvement of adenine nucleotide metabolism and substrates of the xanthine-xanthine oxidase system as the source of oxygen free radicals in a rat model of restrained water immersion stress ulceration. The gastric mucosal concentrations of adenine-5'-triphosphate (ATP), adenine-5'-diphosphate (ADP), adenine-5'-monophosphate (AMP) and thiobarbituric-acid (TBA)-reactant substances were measured after 4, 8 and 12 h restrained water immersion stress. The gastric mucosal concentrations of the nucleoside adenosine, the purine bases xanthine and hypoxanthine, and the final metabolic product uric acid, were measured after 4 h of restrained water immersion stress. The concentrations of ATP diminished significantly after 4, 8 and 12 h of restrained water immersion stress. However, the observed stress-induced changes in ADP were not significant. AMP concentrations increased significantly after 4, 8 and 12 h of stress. The adenylate pool (ATP + ADP + AMP) dropped significantly from the prestress value after 4, 8 and 12 h of stress, and the concomitant energy charge (EC = ATP + 0.5 ADP/ATP + ADP + AMP) decreased significantly after 4 and 8 h of stress compared with the prestress value. Gastric mucosal concentrations of TBA-reactant substances displayed a significant increase after 4 h of stress, and remained unchanged after 8 and 12 h of stress from the level after 4 h. Four hours of restrained water immersion stress induced an increase in adenosine and uric acid concentrations and a decrease in the hypoxanthine concentration of the gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenine Nucleotides; Adenosine; Animals; Anti-Ulcer Agents; Diterpenes; Free Radicals; Gastric Mucosa; Hypoxanthine; Hypoxanthines; Immersion; Male; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Time Factors; Xanthine; Xanthines

Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Repeated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Concerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimuli. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.

Topics: Animals; Anti-Ulcer Agents; Cimetidine; Diterpenes; Duodenal Ulcer; Female; Gastric Mucosa; Gastrointestinal Motility; Guinea Pigs; Immersion; Male; Oximes; Piperazines; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Psychological

Topics: Animals; Anti-Ulcer Agents; Diterpenes; Ethanol; Gastric Mucosa; Rats; Stomach Ulcer; Wound Healing

The effects of teprenone on quantitative changes in gastric mucus glycoprotein during the healing process of acetic acid-induced ulcer in rats were investigated in comparison to those of cimetidine and proglumide. When estimated on the 15th day after operation, teprenone (50 and 100 mg/kg X 2/day, p.o.) significantly decreased the ulcer index by approx. 30%. On the other hand, cimetidine (100 mg/kg X 2/day, p.o.) and proglumide (500 mg/kg X 2/day, p.o.) did not significantly affect it. The high-molecular-weight glycoprotein (HMG, molecular weight of 2 X 10(6) or more) concentration in the gastric mucus of the control group (non-medicated ulcer rats) was 48.7% lower than that of the normal group (non-medicated rats without ulcer). On the contrary, the lower-molecular-weight glycoprotein (LMG, molecular weight between 5 X 10(5) and 2 X 10(6)) concentration of the control group was 95.3% higher than that of the normal group. Teprenone (at both doses) remarkably increased the concentration and secretion of the HMG. In contrast, those of the LMG were decreased by this drug. Cimetidine significantly decreased both the concentration and secretion of the total glycoprotein (HMG + LMG). Proglumide showed only slight increases in the concentration and secretion of the HMG, although it pronouncedly increased the total glycoprotein secretion. These results indicate that teprenone may strengthen the defensive force of gastric mucosa by increasing the HMG with a polymeric structure. In contrast, cimetidine may weaken the mucosal defense.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Cimetidine; Diterpenes; Gastric Mucosa; Glycoproteins; Male; Mucus; Polyenes; Proglumide; Rats; Rats, Inbred Strains; Stomach Ulcer; Wound Healing

The purpose of this study was to investigate the morphological and physiological effects of tetraprenylacetone (TPA) on ethanol(ET)-induced injury in rat gastric mucosa. Fasted rats received orally the following agents; a) vehicle (VH); b) 50, 100, or 200 mg/kg of TPA; c) indomethacin (IDM, 5 mg/kg), 30 min prior to TPA (200 mg/kg). Thirty minutes later, 1 ml of absolute ET was administered into the rat stomach. The gastric mucosa was assessed at 60 min after administration of ET. The ulcer index was significantly decreased by TPA in a dose-related fashion when compared with controls. Histological studies also showed significant reduction of ET-induced mucosal damage by TPA. A scanning electron microscopic study revealed that, when TPA was administered, surface epithelial cells of fundic mucosa were protected against ET-induced injury. The decrease of potential difference induced by ET was diminished by TPA (p less than 0.01). Addition of IDM significantly reduced the effect of TPA. This indicates that TPA has a protective effect on rat gastric mucosa against ET-induced injury. The data also suggested that endogenous prostaglandins may be partially involved in this effect of TPA.

Topics: Animals; Diterpenes; Epithelium; Ethanol; Gastric Mucosa; Indomethacin; Male; Membrane Potentials; Microscopy, Electron, Scanning; Prostaglandins; Rats; Rats, Inbred Strains; Stomach Ulcer

Healing promoting action of teprenone on acetic acid ulcer in rats was assessed in comparison to that of cimetidine and proglumide by histological measurements. Teprenone (100 mg/kg X 2/day, p.o.) decreased the macroscopic ulcer index and the defective area in the ulcerated region by 32.0% and 33.3%, respectively. In addition, this drug increased the decreasing index of exposed ulcer floor and the mucosal regeneration index by 28.1% and 38.0%, respectively. However, the thickness of the ulcer base and the development index of collagen fibers were little affected by this drug. Cimetidine (100 mg/kg X 2/day, p.o.) showed a 27.2% decreasing action on the macroscopic ulcer index and a 31.3% increasing action on the thickness of the ulcer base, but failed to increase the mucosal regeneration index. Specimens from the cimetidine-treated rats were characterized by marked granulation proliferation beneath the ulcer floor. The upper layer of the granulation tissue was very rich in inflammatory cells. Proglumide (250 mg/kg X 2/day, p.o.) was scarcely effective on any parameters. These results indicate that teprenone remarkably promotes the regeneration of the defective mucosa during the ulcer healing process, and the effectiveness of cimetidine according to the macroscopic observation may be due to excessive formation of granulation tissue in the defective region.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Cimetidine; Diterpenes; Male; Polyenes; Proglumide; Rats; Rats, Inbred Strains; Stomach Ulcer

The antiulcer effect of a series of synthetic acyclic polyisoprenoids on cold-restraint stress induced ulcer in female rats was determined, and the relationship between their antiulcer effect and chemical structure was also investigated. As a result, the following findings were obtained: The antiulcer effect of acyclic polyisoprenoids closely correlated with the number of intramolecular isoprene units, and geranylgeranyl derivatives showed a particularly marked antiulcer effect. The terminal polar groups such as 2-oxopropyl and 2-hydroxypropyl groups in geranylgeranylacetone seemed to play an important role in the antiulcer activity of acyclic polyisoprenoids. Terminal bulky groups decreased their antiulcer activity, however. The antiulcer activity of geranylgeranylacetone correlated with the number of intramolecular double bonds. There was no significant difference in antiulcer activity between all-trans-geranylgeranylacetone, 5-cis-geranylgeranylacetone and the mixture of these isomers (1:1 and 3:2). The results of this experiment suggested that the antiulcer activity of acyclic polyisoprenoids might be governed by such factors as the number of isoprene units, terminal polar groups, and number of intramolecular double bonds.

Topics: Animals; Anti-Ulcer Agents; Cold Temperature; Diterpenes; Female; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological; Structure-Activity Relationship; Terpenes

Antiulcer effects of geranylgeranylacetone (GGA) on aspirin-induced gastric ulcers in rats were studied, comparing them with those of gefarnate. The oral administration of GGA prevented the development of gastric ulcer induced by a single or repeated oral administration (5 consecutive days) of aspirin. The effects of GGA were more potent and more definite than those of gefarnate. The intraduodenal administration of GGA, but not the intragastric administration, also inhibited the ulceration induced by aspirin in pylorus-ligated rats, while the intraduodenal administration of gefarnate did not. GGA prevented the reduction of the H+ concentration and the increment of Na+ concentration in the gastric juice induced by aspirin. In addition, the decrease of hexosamine content in the gastric mucosa induced by aspirin was restored to a normal level by GGA, but not by gefarnate. From these results, it was concluded that the protective actions of GGA on aspirin-induced gastric ulcers might be due to its protection from the weakening of gastric mucosal resistances.

Topics: Animals; Aspirin; Diterpenes; Gastric Mucosa; Gefarnate; Hexosamines; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

The effects of various antiulcer drugs and hormones on the cell kinetics of the mouse gastric mucosa were studied using an autoradiographic technique with 3H-thymidine. The drugs or hormones were administered orally or parenterally once or twice a day for 7 consecutive days, and 3H-thymidine was injected after the last administration of the drug. The autoradiograph was prepared and then the labeling index was counted. Cimetidine (100 mg/kg X 2/day, p.o.), geranylgeranylacetone (GGA, 100 mg/kg X 2/day, p.o.) and Cu-chlorophyllin-Na (300 mg/kg X 2/day, p.o.) did not show any effect on the labeling indices in both the tissues of the fundic and pyloric glands, while carbenoxolone (100 mg/kg X 2/day), p.o.) reduced the labeling index in the pyloric glands. Tetragastrin (1 mg/kg X 1/day, i.m.) increased the labeling index in the fundic glands, whereas secretin did not affect it. Hydrocortisone (100 mg/kg X 1/day, S.C.) reduced the labeling index in the fundic glands, and this reducing effect was prevented by combining hydrocortisone with GGA. From these results, it was indicated that the labeling index in the normal mouse gastric generative zone was no influenced by the tested antiulcer drugs, except carbenoxolone; but the index was influenced by tetragastrin and hydrocortisone, especially in the fundic glands. It was also suggested that the changes in the cell kinetics of the gastric mucosa could be related to the etiology of gastric ulcer since there was a possibility that geranylgeranylacetone could control the action of hydrocortisone, an ulcerogenic agent, on the gastric mucosal cell-cycle.

Topics: Animals; Carbenoxolone; Cell Cycle; Chlorophyllides; Cimetidine; Diterpenes; Gastric Mucosa; Gastrins; Hydrocortisone; Kinetics; Male; Mice; Secretin; Stomach Ulcer

Topics: Administration, Topical; Animals; Aspirin; Diterpenes; Hydrochloric Acid; Male; Rats; Rats, Inbred Strains; Stomach Ulcer

Antinuclear effects of geranylgeranylacetone (GGA), new acyclic polyisoprenoid, on several types of experimental gastric and duodenal ulcers were studied in rats. The prophylactic administration of GGA (50--200 mg/kg p.o. or 12.5--50 mg/kg i.p.) reduced the gastric ulcers induced by the exposure to cold-restraint stress and by the administration of indomethacin, acetylsalicylic acid (ASA), prednisolone or reserpine and the duodenal ulcer after the administration of cysteamine, although it was not effective against Shay's ulcer. The curative treatment with GGA accelerated the healing process of the gastric ulcers induced by the topical application of acetic acid or thermocautery and by the administration of ASA with the exposure to cold-restraint stress. The antinuclear effect of GGA was more distinct than that of gefarnate in all types of experimental models studied. Carbenoxolone effectively reduced the gastric ulcer formation by cold-restraint stress when it was administered i.p. but not p.o., whereas GGA was effective either i.p. or p.o. GGA and gefarnate did not affect the gastric secretion in pylorus-ligated rats, whereas carbenoxolone definitely reduced the secretion of gastric juice and acid. Hexosamine content in the stomach was reduced by the exposure to cold-restraint stress. The pretreatment with GGA prevented the reduction in hexosamine contents in the superepithelial mucous layer and mucosal layer. These results may suggest a high possibility that GGA is useful for clinical treatment of peptic ulcers, probably through a mechanism of increasing defence force of the gastric mucosa.

Topics: Animals; Disease Models, Animal; Diterpenes; Duodenal Ulcer; Female; Gastric Acid; Male; Rats; Stomach Ulcer; Terpenes; Wound Healing