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PubMed1996

Synthesis and cytoprotective antiulcer activity of 2- or 4-(1H-pyrazol-1-yl)pyrimidine derivatives related to mepirizole and dulcerozine.

(1H-Pyrazol-1-yl)-, (1H-imidazol-1-yl)-, and (1H-1,2,4-triazol-1-yl)pyrimidines were prepared and evaluated for cytoprotective antiulcer activity. Among them, 4-methoxy-6-methyl-2-(1H-pyrazol-1-yl)pyrimidine (18) showed potent inhibition of the HCl-ethanol-induced and water-immersion stress-induced ulcers in rats, as well as low acute toxicity.

Administration, Oral↗
PubMed1986

Cytoprotective action of mast cell stabilizers against ethanol-induced gastric lesions in rats.

We examined the effects of FPL-52694 and disodium cromoglycate (DSCG), mast cell stabilizers, on HCl X ethanol-induced gastric lesions in rats and investigated the factors involved in their protection. Oral (p.o.) administration of 1 ml of HCl X ethanol (60% in 150 mM HCl) induced linear hemorrhagic lesions in the gastric mucosa within 1 hr. FPL-52694 (1-30 mg/kg), given both p.o. and intraperitoneally (i.p.), prevented these lesions in a dose-related manner. DSCG (3-30 mg/kg) also dose-dependently reduced the formation of these lesions when this agent was given i.p. The protective effects of these drugs on HCl X ethanol-induced lesions were significantly attenuated by pretreatment with indomethacin (5 mg/kg, s.c.). Both gastric acid secretion and transmucosal potential difference were significantly reduced by topical application of FPL-52694 (greater than 10 mg/kg), but were not affected by i.p. administration of FPL-52694 and DSCG. On the other hand, gastric motor activity measured as intraluminal pressure recordings was significantly inhibited for 2 hr by both FPL-52694 (p.o. and i.p.) and DSCG (i.p.), and these effects were also significantly antagonized with prior administration of indomethacin. A significant relationship was found between the effects of these two drugs on the lesion index and the motility index (r: 0.9214, P less than 0.01), but not other factors. These results suggest that mast cell stabilizers such as FPL-52694 and DSCG protect the gastric mucosa against HCl X ethanol through a systemic action, probably mediated with endogenous prostaglandins. Although the mechanism of cytoprotection remains unknown, this property may be related to their inhibitory effects on gastric motor activity.

Animals↗
PubMed1987

Lack of cytoprotection by acetaminophen against ethanol-, HCl.ethanol- and HCl.aspirin-induced gastric mucosal lesions in rats.

Effects of acetaminophen against gastric mucosal lesions induced by three different necrotizing agents were studied. Acetaminophen (30, 100 mg/kg), given p.o. 0.5 hr before absolute ethanol, HCl . ethanol, or HCl . aspirin administration, afforded no cytoprotection against gastric mucosal lesions induced by the above agents in 24 hr fasted rats. However, 16,16-dimethyl prostaglandin E2 (3 micrograms/kg), given p.o. 0.5 hr before these necrotizing agents, completely prevented development of these lesions.

16,16-Dimethylprostaglandin E2↗
PubMed1987

Roles of gastric motility changes in cytoprotection induced by acetazolamide and cysteamine in rats.

The present study was undertaken using acetazolamide (AZ) and cysteamine (Cys) to investigate the relationship between gastric motor activity and the phenomenon of "cytoprotection" in rats. Both AZ (10-100 mg/kg) and Cys (10-100 mg/kg), given either p.o. or s.c., significantly reduced the formation of gastric mucosal injury caused by HCl-ethanol (1 ml of 60% ethanol in 150 mM HCl, p.o.). The protective effect of Cys appeared within 10 min, reached the maximal levels 30 min later, while that of AZ appeared from 30 min after administration and became potent with a latency period after treatment. Neither indomethacin (IM: 5 mg/kg, s.c.) nor N-ethylmaleimide (NEM: 5 mg/kg, s.c.) significantly affected the protective effect of Cys, whereas that of AZ was almost totally antagonized by IM. Both AZ and Cys, given either intragastrically or s.c., significantly inhibited gastric motor activity measured as intraluminal pressure recordings, but had minimal effect on acid and alkaline secretion. IM significantly attenuated the inhibitory effect of AZ on the motor activity, while NEM did not affect the inhibited motor responses caused by AZ and Cys. A significant relationship was found between the inhibitory effects of these two drugs on gastric motor activity and HCl-ethanol-induced mucosal injury, the correlation coefficient being 0.819 (P less than 0.01). When the mucosal folds were visualized with Gentian Violet (1 ml of 0.5% v/v, p.o.), both AZ and Cys significantly prevented the localized staining along the mucosal folds, suggesting dissolution of the folds. These results suggest that both AZ and Cys protect the gastric mucosa against injury caused by HCl-ethanol, probably through a dissolution of mucosal folds due to inhibition of gastric motor activity.

Acetazolamide↗
PubMed1988

Cytoprotective action of cetraxate against HCl.ethanol-induced gastric lesion in rats.

The protective effect of cetraxate, an antiulcer and antigastritis agent, on HCl.ethanol-induced gastric lesions was investigated in rats. Oral administration of 1 ml of HCl.ethanol (60% ethanol in 150 mM HCl) induced within 1 hr linear hemorrhagic necrosis in the gastric mucosa. Either oral or intraperitoneal treatment with cetraxate (30-300 mg/kg) significantly inhibited such macroscopic gastric lesions in a dose-related manner, and the inhibition at the oral highest dose (300 mg/kg) was practically complete. Histological analysis also confirmed that cetraxate effectively prevented deep mucosal necrosis, but showed that it was without protective effect on the surface epithelial disruption and submucosal edema in response to HCl.ethanol. The antilesion activity of cetraxate was of statistically significance for at least 3 hr after a single injection, and it was hardly affected by the removal of the gastric contents just prior to application of the necrotizing agent. However, subcutaneous treatment of rats with indomethacin (5 mg/kg) resulted in a partial but significant attenuation in the protection afforded by cetraxate, suggesting that dual mechanisms related and unrelated to endogenous prostaglandins may be involved in its protective activity. The results demonstrate that cetraxate is a potent cytoprotective agent effectively preventing the formation of gastric mucosal necrosis induced by HCl.ethanol.

Animals↗
PubMed1991

Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach.

We have examined the effect of orally administered capsaicin on gastric motility in the rat to investigate a possible relationship between motility change and cytoprotection induced by this agent. Capsaicin, given orally (1-30 mg/kg), dose-dependently inhibited hemorrhagic band-like lesions induced by ethanol (60% in 150 mM HCl). This protection was significantly mitigated by desensitization of afferent neurons following capsaicin pretreatment 2 weeks before the experiment, and it was also significantly attenuated by prior administration of indomethacin, but not by spantide. Intragastric administration of capsaicin (30 mg/kg) significantly inhibited gastric motility and increased the mucosal blood flow, but had no effect on the transmucosal potential difference of the stomach. These functional changes induced by capsaicin were also less marked in the afferent neuronal desensitized rat, and they were significantly attenuated by indomethacin but not by spantide. These results suggest that the mucosal protection by intragastric capsaicin may be associated with the inhibition of gastric motility and the increase of mucosal blood flow. These responses may be induced by activation of primary afferent neurons which are probably sensitized by endogenous prostaglandins.

Animals↗
PubMed1993

NC-1300, a proton-pump inhibitor, requires gastric acid to exert cytoprotection in rat gastric mucosa.

Effect of gastric acid suppression on the cytoprotective effect of a single dose of NC-1300 given intragastrically was studied. NC-1300 given intragastrically prevented gastric mucosal damage caused by absolute ethanol in rats in a dose-related manner, while the drug given subcutaneously did not. Pretreatment with NC-1300 given subcutaneously to suppress acid secretion abolished the protective effect of NC-1300 given intragastrically, but not in the presence of 0.1 N HCl. Repeated intragastric administration of NC-1300 for 7 days failed to prevent the ethanol damage. These results suggest that NC-1300 requires gastric acid to exert a protective effect against ethanol in rat gastric mucosa.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

The N. gonorrhoeae type IV pilus stimulates mechanosensitive pathways and cytoprotection through a pilT-dependent mechanism.

The Neisseria gonorrhoeae type IV pilus is a retractile appendage that can generate forces near 100 pN. We tested the hypothesis that type IV pilus retraction influences epithelial cell gene expression by exerting tension on the host membrane. Wild-type and retraction-defective bacteria altered the expression of an identical set of epithelial cell genes during attachment. Interestingly, pilus retraction, per se, did not regulate novel gene expression but, rather, enhanced the expression of a subset of the infection-regulated genes. This is accomplished through mitogen-activated protein kinase activation and at least one other undefined stress-activated pathway. These results can be reproduced by applying artificial force on the epithelial membrane, using a magnet and magnetic beads. Importantly, this retraction-mediated signaling increases the ability of the cell to withstand apoptotic signals triggered by infection. We conclude that pilus retraction stimulates mechanosensitive pathways that enhance the expression of stress-responsive genes and activate cytoprotective signaling. A model for the role of pilus retraction in influencing host cell survival is presented.

Adenosine Triphosphatases↗
PubMed2002

The heat shock response and cytoprotection of the intestinal epithelium.

Following heat stress, the mammalian intestinal epithelial cells respond by producing heat shock proteins that confer protection under stressful conditions, which would otherwise lead to cell damage or death. Some of the noxious processes against which the heat shock response protects cells include heat stress, infection, and inflammation. The mechanisms of heat shock response-induced cytoprotection involve inhibition of proinflammatory cytokine production and induction of cellular proliferation for restitution of the damaged epithelium. This can mean selective interference of pathways, such as nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK), that mediate cytokine production and growth responses. Insight into elucidating the exact protective mechanisms could have therapeutic significance in treating intestinal inflammations and in aiding maintenance of intestinal integrity. Herein we review findings on heat shock response-induced intestinal epithelial protection involving regulation of NF-kappaB and MAPK cytokine production.

Animals↗
PubMed2006

Desensitized nicotinic receptors that, however, afford cytoprotection in bovine chromaffin cells.

Neuronal nicotinic receptors for acetylcholine (nAChRs) are among the ionotropic receptors that suffer the most desensitization upon prolonged exposure to their agonists. This is particularly true for the alpha7 subtype of nAChRs, although alpha3beta4 receptors also suffer quick desensitization. This study was planned to test the hypothesis that even after suffering desensitization, a given nAChR might still afford cell protection against a noxious stimulus. Of the many agonists developed for nAChRs, we selected the poorly desensitizing ligand dimethylphenylpiperazinium (DMPP) (Britt and Brenner, 1997) and the highly desensitizing agent epibatidine (EPB) (Marks et al., 1996). We have measured nAChR currents, catecholamine secretory responses, and changes of [Ca2+]c elicited by stimulation of nAChRs with DMPP or EPB. We have also investigated cytoprotection elicited by DMPP and EPB against the cytotoxic effects of veratridine in bovine chromaffin cells.

Adrenal Glands↗
PubMed2006

Cytoprotection by pyruvate through an anti-oxidative mechanism in cultured rat calvarial osteoblasts.

Although we have previously shown drastic cell death by pyruvate deficiency in osteoblasts at the proliferative stage, the exact mechanism remains unclear so far. Cell survivability was significantly decreased in rat calvarial osteoblasts cultured for 0 to 3 days in vitro (DIV) following replacement of the eutrophic alpha-modified minimum essential medium (alpha-MEM) with Dulbecco's modified eagle medium (DMEM) for cultivation. The addition of pyruvate enriched in alpha-MEM, but not in MEM, entirely prevented cell death induced by the medium replacement throughout a culture period from 0 to 3 DIV. Both cysteine and reduced glutathione protected cell death in cells cultured for 3 DIV without significantly affecting that in cells cultured for 1 DIV, however, while none of lactate, acetate and insulin significantly prevented the cell death irrespective of the culture period up to 3 DIV. A marked increase was detected in intracellular reactive oxygen species (ROS) levels 4 h after the medium replacement. In osteoblasts cultured in alpha-MEM for 3 DIV, but not in those for 7 DIV, hydrogen peroxide (H2O2) markedly decreased cell survivability when exposed for 2 to 24 h. Furthermore, H2O2 was effective in significantly decreasing cell survivability in osteoblasts cultured in DMEM for 7 DIV. Pyruvate at 1 mM not only prevented cell death by H2O2, but also suppressed the generation of intracellular ROS in osteoblasts exposed to H2O2. These results suggest that pyruvate could be cytoprotective through a mechanism associated with the anti-oxidative property rather than an energy fuel in cultured rat calvarial osteoblasts.

Animals↗
PubMed2004

Clinical trials for cytoprotection in stroke.

To date, many cytoprotective drugs have reached the stage of pivotal phase 3 efficacy trials in acute stroke patients. (Table 1) Unfortunately, throughout the neuroprotective literature, the phrase "failure to demonstrate efficacy" prevails as a common thread among the many neutral or negative trials, despite the largely encouraging results encountered in preclinical studies. The reasons for this discrepancy are multiple, and have been discussed by Dr. Zivin in his review. Many of the recent trials have addressed deficiencies of the previous ones with more rigorous trial design, including more specific patient selection criteria (ensure homogeneity of stroke location and severity), stratified randomization algorithms (time-to-treat), narrowed therapeutic time-window and pharmacokinetic monitoring. Current trials have also incorporated biologic surrogate markers of toxicity and outcome such as drug levels and neuroimaging. Lastly, multi-modal therapies and coupled cytoprotection/reperfusion strategies are being investigated to optimize tissue salvage. This review will focus on individual therapeutic strategies and we will emphasize what we have learned from these trials both in terms of trial design and the biologic effect (or lack thereof) of these agents.

Animals↗
PubMed1986

Pathogenesis of peptic ulcer disease and gastritis: importance of aggressive and cytoprotective factors.

Acid production is a major gastric function. Second messengers (cyclic AMP and calcium) are released when parietal cell membrane receptors (H2, muscarinic and gastrin) are stimulated. The second messengers then stimulate the 'gastric proton pump' to produce hydrogen ions. New evidence suggests that there is a unidirectional flux of hydrogen ions into the lumen induced by unique physical properties of mucus and a sodium gradient from lumen to serosa. Luminal hydrogen ions, bile salts, ingested drugs, and ingested alcohol are potential gastric epithelial toxins. The stomach's protective mechanism includes a well-defined mucus layer, an epithelial bicarbonate secretion, a tight epithelium, and a good nutrient blood supply. Endogenous prostaglandins partly control these mechanisms. Modern therapeutics are increasingly directed towards improving gastric cytoprotection.

Gastric Acid↗
PubMed1987

Cytoprotection by sucralfate in acid-exposed esophagus: a review.

Sucralfate is protective against acid or acid-pepsin injury to rabbit and cat esophagus. Its beneficial action is due in part to enhanced mucosal defense (cytoprotection) since it can occur in the absence of luminal buffering of hydrogen ion. The limited prospect for this effect to be prostaglandin-mediated is discussed and candidate mechanisms for its action enumerated.

Animals↗
PubMed1992

Non-steroidal anti-inflammatory drug gastropathy and cytoprotection: pathogenesis and mechanisms re-examined.

Gastric and intestinal injury induced by non-steroidal anti-inflammatory drugs (NSAIDs) is a common and expensive adverse effect of this class of drugs. While it is likely that inhibition of prostaglandin synthesis by these agents is an important component of their ulcerogenic properties, the pathogenesis of NSAID gastropathy remains unclear. Likewise, the underlying mechanism for prostaglandin 'cytoprotection' is not fully understood, although it is clear from recent clinical trials that prostaglandin analogues are an effective treatment to prevent NSAID gastropathy. In this paper the contribution of neutrophils to the mucosal damage induced by NSAIDs is discussed, as is the possibility that prostaglandins protect the gastrointestinal mucosa from NSAID-induced ulceration at least in part through inhibitory effects on neutrophil function.

Animals↗
PubMed1992

Role of gastric mucosal eicosanoid production in the cytoprotection induced by nitecapone.

Nitecapone (3-100 mg/kg orally) dose-dependently (40-97%) decreased the macroscopic gastric lesions induced by ethanol, NaOH, or HCl in the rat. The duration of protection was long, being still 70% at 6 h after dosing. Nitecapone (10-100 mg/kg orally) induced at 1 h after dosing a significant and dose-dependent increase in gastric mucosal prostaglandin E2 release. After the dose of 30 mg/kg the release was sixfold at 2 h and threefold at 12 h. Colloidal bismuth subcitrate (30 mg/kg) stimulated the prostaglandin E2 release only transiently, and sucralfate (400 mg/kg) showed only a tendency to stimulate the release. Indomethacin prevented the nitecapone-induced stimulation of prostaglandin E2 but was unable to counteract the cytoprotective activity of the compound. Nitecapone (30 mg/kg) also caused transient increase (twofold) in the release of 6-keto-prostaglandin F1 alpha and thromboxane B2 and a decrease in both basal and ethanol-induced release of leukotriene C4.

Animals↗
PubMed2006

Polaprezinc protects human colon cells from oxidative injury induced by hydrogen peroxide: relevant to cytoprotective heat shock proteins.

AIM: To investigate the effect of polaprezinc on cellular damage induced by hydrogen peroxide (H(2)O(2)) in human colon CaCo2 cells. METHODS: CaCo2 cells were treated with polaprezinc (10-100 micromol/L) for 6 h. After polaprezinc treatment, the cells were incubated with H(2)O(2) (20 micromol/L) for 1 h. Cell viability was measured by MTT assay. Western blot analysis for heat shock protein (HSP) 27 and HSP72 in the cells was performed. Moreover, cells were pretreated with quercetin (200 micromol/L), an inhibitor of HSP synthesis, 2 h before polaprezinc treatment, and cell viability and the expression of HSP27 and 72 were assessed in these cells. RESULTS: Polaprezinc significantly protected CaCo2 cells from cell damage induced by H(2)O(2), and up-regulated the expressions of HSP27 and HSP72 in the cells (10, 30 and 100 micromol/L of polaprezinc; 35.0% +/- 7.7%, 58.3% +/- 14.6% and 64.2% +/- 8.2%, respectively. P < 0.01 versus polaprezinc-nontreated cells; 6.0% +/- 4.4%). Quercetin inhibited the up-regulation of HSP27 and HSP72 by polaprezinc and diminished the protective effect of polaprezinc against H(2)O(2)-caused injury in the cells. CONCLUSION: Polaprezinc is a useful therapeutic agent for treatment of colitis and its effects depend on the function of cytoprotective HSP in colon.

Anti-Ulcer Agents↗
PubMed1993

Thiazohalostatin, a new cytoprotective substance produced by Actinomadura. I. Taxonomy, production, isolation and biological activities.

Thiazohalostatin has been isolated from the culture broth of Actinomadura sp. by a screening program designed to find novel cytoprotective substances. It was purified by use of column chromatography on silica gel, reversed phase HPLC and then isolated as colorless powder. Thiazohalostatin prevented cell death caused by calcium overload and exhibited an inhibitory activity against lipid peroxidation.

Actinomycetaceae↗