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PubMed1994

Cytoprotection: concepts and challenges.

Clinical trials with several toxicity protectors (cytoprotective or chemoprotective agents) have been performed during the past decade. These trials are quite complex since they must include sufficient dose-limiting events for study, and assessment of both toxicity (and therefore the efficacy of protection) and antitumor effects must be carried out. However, it is inevitable that with greater understanding of drug actions, one seeks to manipulate these for greater antitumor activity (biochemical modulation) or for lesser dose-limiting toxicity (cytoprotection) or for both. Examples of cytoprotective agents include dexrazoxane (ICRF-187), protecting against doxorubicin cardiotoxicity, and amifostine protecting against the myelosuppression of platinum and alkylating agents. In spite of the challenges encountered in the clinical development of these drugs, studies of cytoprotectors have led to a considerable understanding of important therapeutic issues and tangible clinical benefit in specific clinical situations.

Antineoplastic Agents↗
PubMed1987

Mucosal coating agents and other nonantisecretory agents. Are they cytoprotective?

Gastric cytoprotection is protection against gross and histological gastric mucosal injury by a mechanism other than inhibition of neutralization of gastric acid secretion. Animal studies have shown that a variety of agents afford such a protective effect. With some of these agents, a similar protective effect has been shown in man. This protective effect must be distinguished from an action that enhances healing of an already established mucosal lesion as an ulcer. It is yet to be established that the cytoprotective effect of an agent enhances ulcer healing. Agents other than prostaglandins that have been shown to possess such a cytoprotective effect in animals are reviewed. Some, such as sucralfate, act via stimulation of endogenous prostaglandin synthesis, while others, such as DeNol, neomycin, and meciadanol, do not. Investigation of the mechanism through which these agents enhance gastric mucosal defense is a fertile field for investigation.

Animals↗
PubMed1990

Evaluation of putative cytoprotective properties of antiulcer drugs using quantitative histological techniques.

The capacity for cytoprotection has been claimed for a number of drugs that may have a place in the treatment of peptic ulcer disease. In this study we have used quantitative histological criteria to evaluate the ability of these drugs to be cytoprotective and have compared their effects with that of natural prostaglandin E2 (PG). The standard rat model, with injury by instillation of 1 ml of absolute ethanol, has been used. Putative cytoprotective agents were administered 15 min prior to ethanol. Each animal was sacrificed 15 min after ethanol exposure. The stomach was removed and studied using an established quantitative histological technique. This technique provides a measure of the surface area of mucosa damaged and of the volume of mucosa damaged. Ethanol alone caused damage to 76% of the area of the rat stomach and 14% of the volume of the rat gastric mucosa. Pretreatment by PG (25 micrograms/ml) resulted in reduction of the area of damage to 45% and reduction of the percentage volume damage to 2.2%. The synthetic analog of PGE2, Enprostil (1 microgram/ml) achieved similar protective effects. With pretreatment with colloidal bismuth subcitrate (10 mg/kg) or sucralfate (25 mg/kg), no protection against the surface area damaged by ethanol was seen, but there was a marked reduction of the volume of mucosa damaged. Indomethacin pretreatment augmented the damage caused by ethanol. The protective effects of colloidal bismuth subcitrate and sucralfate were not blocked by pretreatment with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Gastric cytoprotection: a critical appraisal of the concept, methodology, implications, mechanisms and future research prospects.

Gastric cytoprotection is the property of certain substances, particularly prostaglandins, when used in non-antisecretory doses, to protect the gastric mucosa from becoming inflamed and necrotic on being exposed to noxious agents. An association between alterations in endogenous prostaglandins and gastric mucosal damage induced by a number of drugs has also been observed. The process of adaptive cytoprotection in which mild irritants protect the gastric mucosa against the damaging effects of various necrotizing agents has been shown to be prostaglandin mediated. However, the exact mechanisms underlying this cytoprotective activity have still not been elucidated although a number of hypotheses have been proposed. Recently, thromboxanes, leukotrienes and endogenous sulfhydryls have also been suggested to be involved in the pathogenesis of gastric mucosal damage induced by various necrotizing agents. This review attempts to provide an up-to-date appraisal of the concept, methodology, mechanisms and implications of this phenomenon and suggests that prostaglandins and endogenous sulfhydryls may play a significant role in the pathogenesis of gastric ulceration and may serve an important function in maintaining normal gastric mucosal integrity.

Animals↗
PubMed1996

Mechanisms for cytoprotection by vitamin U from ethanol-induced gastric mucosal damage in rats.

A comparison was made of the effects of a nonsulfhydryl compound, vitamin U (methylmethioninesulfonium chloride, MMSC), and a sulfhydryl compound, cysteine (Cys), with regard to the inducement of acute gastric mucosal damage in the presence and absence of N-ethylmaleimide (NEM), a sulfhydryl-blocking reagent. The effects of MMSC, Cys, or NEM on gastric mucin content were examined using a newly developed biochemical method. MMSC and Cys inhibited mucosal damage due to 50% ethanol. The preinjection of NEM had no effect on cytoprotection of prostaglandins, but prevented the effects of Cys and MMSC. MMSC and Cys increased surface mucin content but lessened that of deep mucin. NEM decreased surface mucin and increased deep mucin. It thus follows that sulfhydryl compounds accelerate the secretion of deep mucin and accumulate surface mucin. The cytoprotective mechanism of MMSC may thus be mediated by sulfhydryl compounds, and the increase in surface mucosal mucin may possibly be related to cytoprotection.

Animals↗
PubMed2004

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats.

BACKGROUND: Portal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats. METHODS: PHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6 N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups. RESULTS: Portal venous pressure was significantly higher in cirrhotic rats compared with control rats ( P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress. CONCLUSIONS: These findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.

Animals↗
PubMed1993

Role of nitric oxide in the gastric cytoprotection induced by central vagal stimulation.

The role of nitric oxide (NO) in the vagal cholinergic-mediated cytoprotective effect of intracisternal (i.c.) injection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, was investigated in conscious rats. RX 77368 (1.5 ng i.c.) reduced by 88% gastric hemorrhagic lesions induced by oral administration of ethanol (60%). L-NG-Nitro-arginine methyl ester (L-NAME, 3 mg/kg i.v.), an inhibitor of NO synthase, abolished the cytoprotection provided by i.c. RX 77368. The effect of L-NAME was reversed by L- but not D-arginine. These results suggest that the L-arginine-nitric oxide pathway is involved in the cytoprotective effect of i.c. TRH analog, probably through the modulation of gastric mucosal blood flow.

Amino Acid Oxidoreductases↗
PubMed1995

Cytoprotective effects of CI-959 in the rat gastric mucosa: modulation of leukocyte adhesion.

BACKGROUND & AIMS: CI-959 is an anti-inflammatory agent that inhibits neutrophil adhesion, respiratory burst, and mast cell histamine release in vitro. In view of the emerging role of neutrophils in gastric erosive damage, the goals of this study were to assess the gastric cytoprotective effects of CI-959 and identify the mechanism responsible for this action. METHODS: Cytoprotective effects in the rat nonsteroidal anti-inflammatory drug and ethanol erosion models were assessed using image analysis. The in vivo effects of CI-959 on gastric acid secretion, arachidonic acid metabolism, and intracellular sulfhydryl and leukocyte adhesion were also examined. RESULTS: CI-959 protected prophylactically against the erosive damage induced by aspirin, indomethacin, and ethanol with 50% effective doses (ED50s) of 0.05, 1.0, and 0.07 mg/kg administered orally, respectively. When administered after indomethacin or ethanol, CI-959 had no effect on the healing of erosive damage. CI-959 did not alter gastric acid secretion, arachidonic acid metabolism, or intracellular sulfhydryl levels. In vivo, CI-959 blocked leukocyte adhesion in intravital microscopy studies using indomethacin (ED50, < 5 mg/kg orally) or platelet-activating factor (50% inhibiting concentration, approximately 10 mumol/L) as the adhesion stimulus. CONCLUSIONS: The most likely mechanism responsible for the cytoprotective effects of CI-595 is its inhibitory effects on leukocyte trafficking and/or adhesion.

Animals↗
PubMed1995

Endogenous mediators in adaptive cytoprotection against ethanol-induced gastric gland damage in rabbits.

The present study determined the participation of different endogenous mediators in adaptive cytoprotection against gastric gland damage caused by ethanol in rabbits. Using the isolated gland preparation, pretreatment with 10(-5)M of either indomethacin, Nw-nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM), but not of substance P antagonist, intensified the 10% (v/v) ethanol-induced gastric gland damage and lessened the degree of cytoprotection evoked by 2% (v/v) ethanol to a significant level. Co-administration with 10(-4)M of prostaglandin E2, L-arginine or glutathione to the respective groups completely reversed the above adverse effects. These results demonstrate the involvement of endogenous prostaglandins, nitric oxide and glutathione in gastric adaptive cytoprotection against the damaging action of ethanol in the rabbit gastric glands.

Adaptation, Physiological↗
PubMed1994

A putative cytoprotective receptor in the kidney: relation to the neuronal strychnine-sensitive glycine receptor.

The neutral amino acid glycine has been demonstrated to prevent cell death in numerous cell types exposed to a variety of toxic insults. Recently, the central nervous system (CNS) glycine antagonist strychnine was demonstrated to bind specifically to the plasma membrane of renal proximal tubules (RPT) and mimic glycine cytoprotection. Further, it has been demonstrated in RPT that glycine and strychnine block chloride influx in the late stages of cell injury. The aim of this study was to determine if the RPT cytoprotective site is related to neuronal glycine receptors. Only antagonists to the CNS strychnine-sensitive glycine receptor (strychnine, brucine), and not antagonists to the glycine modulatory site of the NMDA receptor (DCQX, 7-CKA, HA-966) or the GABAA receptor (bicuculline methiodide, picrotoxin), prevented mitochondrial inhibitor (antimycin A)-induced RPT cell death. Using immunoblot analysis, proteins corresponding to the 58 kDa beta-subunit of the strychnine-sensitive glycine receptor and the associated protein gephyrin were identified in rabbit kidney cortical membrane fractions and RPT. No protein corresponding to the 48 kDa alpha-subunit was identified. Thus, glycine and strychnine may exert their cytoprotective effects via a putative plasma membrane receptor that is related to the strychnine-sensitive glycine receptor found in the CNS.

Animals↗
PubMed1995

Contributions of physical and chemical properties of mild irritants to gastric cytoprotection in rats.

The present study demonstrated the cytoprotective abilities of low concentrations of ethanol, NaCl and HCl, against the gastric mucosal damage caused by 100% ethanol, and the contributions of the physical and chemical properties of these mild irritants to their protective actions. The results have shown the differential protective effects of ethanol (10-40%), NaCl (2.5-12.5%) and HCl (0.15-0.45M), with the optimal cytoprotective concentrations being 20% ethanol, 5% NaCl and 0.3M HCl, respectively. Solutions of KCl and NaCl with similar osmolarity, and H2SO4 and HCl of similar acidity and osmolarity, all showed similar protective protective potentials as compared to the osmotic agent mannitol, which possessed a concentration- and tonicity-dependent protective action against 100% ethanol-induced mucosal damage. Some concentration of methanol, propan-2-ol and ethanol, having similar osmolarity with deionized water, exerted indifferent protective effects. It is therefore concluded that adaptive cytoprotection induced by low concentrations of NaCl and HCl could depend on their physical properties, while that of ethanol could act through its unique chemical property.

Animals↗
PubMed1988

Gastric anti-ulcer and cytoprotective effect of selenium in rats.

Selenium, a trace element, in the form of sodium selenite has been studied for its ability to protect the gastric mucosa against the injuries caused by hypothermic restraint stress, aspirin, indomethacin, reserpine, dimaprit, and various other gastric mucosal-damaging (necrotizing) agents in rats. The results demonstrate that oral administration of sodium selenite produces a significant inhibition of the gastric mucosal damage induced by all the procedures used in this study. Selenium, in a nonantisecretory dose, produced a marked cytoprotective effect against all the necrotizing agents. The cytoprotective effect of selenium against the effects of 80% ethanol and 0.6 M HCl was significantly reversed by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis. These data indicate that sodium selenite inhibits the formation of these lesions by the mucosal generation of prostaglandins. The concentrations of nonprotein sulfhydryls (NP-SH) were significantly decreased in the gastric mucosa following the administration of necrotizing agents--80% ethanol and 0.6 M HCl. Treatment with sodium selenite, which significantly reduced the intensity of gastric lesions, did not replenish the reduced levels of gastric mucosal NP-SH, thus ruling out the mediation of its protective effect through sulfhydryls. The antisecretory effect of sodium selenite, which becomes evident only in the high dose of 20 mumol/kg, may be responsible for the inhibition of gastric lesions induced by aspirin, indomethacin, reserpine, and dimaprit. Our findings show that selenium possesses significant anti-ulcer and adaptive cytoprotective effects. However, further detailed studies are required to confirm these effects, to establish its mechanism(s) of action, and to determine its role in the prophylaxis and treatment of peptic ulcer disease.

Administration, Oral↗
PubMed1989

Phenobarbital-induced cytosolic cytoprotective mechanisms that offset increases in NADPH cytochrome P450 reductase activity in menadione-mediated cytotoxicity.

Hepatocytes isolated from phenobarbital (PB)-pretreated and naive male Sprague-Dawley rats were incubated with menadione under one of three oxygen conditions (0, 21, or 95% oxygen) for 3 hr. During this time, samples were drawn and assayed for lactate dehydrogenase release and trypan blue exclusion as indices of cytotoxicity. Neither parameter indicated any significant difference in menadione-induced cytotoxicity between naive and PB-pretreated hepatocytes. Likewise, no difference was observed between hepatocytes incubated in 21% versus 95% O2. Consistent with the oxyradical hypothesis of menadione-induced cytotoxicity, hepatocytes incubated under 0% O2 (95:5; N2:CO2) did not exhibit any menadione cytotoxicity. Hepatic microsomes prepared from PB-pretreated rats exhibited a threefold increase in NADPH cytochrome P450 reductase activity over those of controls. Menadione-stimulated superoxide (O2-) production was twofold higher in PB pretreated versus naive liver microsomes. However, PB pretreatment failed to produce an increase in O2- production in intact hepatocytes or in hepatocytes disrupted by sonication. The failure of PB pretreatment to increase menadione-induced cytotoxicity and superoxide production in either intact or sonicated hepatocytes suggests that a concomitant cytoprotective mechanism is induced as well. The data further indicate that the cytoprotective elements are located in a nonmicrosomal fraction of the cell. In support of this, we observed PB-induced increases in glutathione levels, glutathione reductase, and DT-diaphorase activities. These findings indicate that PB-induced enhancements of the hepatocellular cytoprotective mechanisms collectively compensate for the increased redox cycling mechanism, resulting in a mitigation of the anticipated increased hepatocellular cytotoxicity of menadione.

Animals↗
PubMed1981

Gastric cytoprotection by sodium salicylate.

Sodium salicylate (SA), contrary to acetylsalicylic acid (ASA, aspirin), was not ulcerogenic in rats. SA was also found to be cytoprotective: it prevented formation of gastric mucosal necrosis produced by either absolute ethanol or 0.6 M HCl, and formation of gastric ulcers produced by acidified ASA. The degree of protection was dose dependent. The mechanism of this cytoprotection is unknown, but unlike cytoprotection elicited by mild irritants, e.g., 20% ethanol or 0.35 M HCl, whose effects appear to be due to endogenous formation of PG by the stomach, SA acts through a different mechanisms, since its protective effect was not blocked by indomethacin.

Animals↗
PubMedDate not supplied

Coprescribing of nonsteroidal anti-inflammatory drugs and cytoprotective and antiulcer drugs in Nova Scotia's senior population.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for the elderly and are commonly prescribed with cytoprotective or antiulcer drugs to prevent or treat gastrointestinal side effects. The objective of this study was to examine the utilization and drug costs of NSAIDs, and to examine coprescription of cytoprotective and antiulcer drugs with NSAIDs in the Nova Scotia population aged 65 years and older. The study used data from the Nova Scotia Seniors Pharmacare program database, which contains data on claims for all filled prescriptions to persons 65 years of age and older. We examined claims for the period April 1, 1993, to March 31, 1994. Aspirin accounted for the largest percentage of the total days supply of NSAIDs (25.2%), followed by diclofenac (18.8%) and naproxen (12.9%). Diclofenac accounted for the largest share of expenditures for NSAIDs (27.6%). Overall, 17.1% of the total days supply of NSAIDs were coprescribed with a cytoprotective or antiulcer drug. Histamine2 blockers accounted for most coprescribed days supply (83.6%) followed by sucralfate (8.1%), misoprostol (4.5%), and omeprazole (2.3%). The appropriateness and cost-effectiveness of these coprescriptions must be examined.

Aged↗
PubMed1991

Cytoprotective effect of reduced glutathione in arsenical-induced endothelial cell injury.

The effect of four arsenic compounds on cultured endothelial cell isolated from bovine carotid arteries was studied. Only trivalent arsenicals (arsenic trioxide and sodium m-arsenite), but not pentavalent arsenicals (arsenic acid and p-arsenilic acid), induced significant cell injury. Since the intracellular reduced glutathione (GSH) plays an important role in detoxication in mammalian cells, its effect on arsenical-induced cell injury was then studied. Pretreatment of cells with 500 microM GSH not only resulted in several-fold increase in the intracellular level of GSH but also effectively protected them against the injury caused by arsenic trioxide. After a pretreatment of cells with GSH for 3 h, the intracellular GSH reached a plateau. A longer pretreatment for 24 h still kept GSH at a very significant high level. The cell injury induced by arsenic trioxide was protected by GSH, and then cellular biosynthesis of PGI2 in culture was also increased. The cytoprotective effect and the stimulatory effect on PGI2 production, where both were dose-dependent on GSH, were in a strict reverse relationship. Aspirin treatment inhibited the PGI2 biosynthesis induced by GSH in the arsenic trioxide-induced cell injury, and significantly reduced the cytoprotective effect induced by GSH. These results suggest that the marked stimulation of endogenous PGI2 biosynthesis by GSH is the mechanism of the latter's cytoprotective effect on arsenic trioxide-induced endothelial cell injury.

Animals↗
PubMed1992

Cytoprotective effect of reduced glutathione in hydrogen peroxide-induced endothelial cell injury.

The kinetic effects of hydrogen peroxide (H2O2) on cultured endothelial cells isolated from bovine carotid artery were studied. The cytoprotective effects of glutathione (GSH) on H2O2-induced cell injury were also investigated. H2O2-induced a dose- and time-dependent cell injury in cultured endothelial cells. H2O2-induced cell injury was blocked by simultaneous treatment by catalase, but not by superoxide dismutase. H2O2 also induced endogenous PGI2 biosynthesis, and the maximum PGI2 production was reached after 1 h treatment. Stimulation of PGI2 production was parallel with arachidonate release from H2O2-treated cells. However the prostaglandin biosynthesis enzyme activity in cells was inhibited by H2O2 treatment. When the cells were treated with GSH, the intracellular GSH reached a plateau after 3 h treatment. Both H2O2-induced cell injury and PGI2 production were significantly inhibited by the 3 h pretreatment with GSH. The cytoprotective effect of GSH was completely inhibited by buthionine sulfoximine which is a specific inhibitor of gamma-glutamylcysteine synthetase. The results indicate that the cytoprotective effect of GSH on H2O2-induced cell injury in cultured bovine carotid artery endothelial cells depends on the increase in intracellular GSH content.

Animals↗
PubMed2004

NO suppresses while peroxynitrite sustains NF-kappaB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

OBJECTIVE: NO has both cytoprotective and cytotoxic effects. A key cytoprotective action of NO is attributed to inhibition of nuclear factor-kappaB (NF-kappaB)-mediated gene expression; this potentially endows NO with ubiquitous anti-inflammatory activity. Since immunostimulant-induced iNOS gene expression is itself dependent on NF-kappaB, NO is expected to limit its own synthesis. On the other hand, many cytotoxic actions of NO have been attributed to the chemical reactivity of peroxynitrite (ONOO-) formed from NO by near diffusion-limited reaction with O2-. To assess whether ONOO- shares the ability of NO to inhibit NF-kappaB activation and consequent iNOS gene expression, we compared effects of NO donors (NOR3 and SNAP), an ONOO- donor (SIN-1), and pure ONOO- on LPS-induced responses in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: NO donors, but not ONOO-, suppressed LPS-induced NF-kappaB activation and expression of a murine iNOS promoter/reporter construct. An NO donor also suppressed NF-kappaB activation when induced by IL-1beta or TNFalpha. Northern blot and RT-PCR analyses showed that NO, but not ONOO- or 8-bromo-cGMP, decreases LPS-induced expression of iNOS mRNA. Electrophoretic mobility shift assays (EMSA) and immunocytochemical analyses confirmed that NO but not ONOO- inhibits nuclear translocation of NF-kappaB. Although ONOO- generation from SIN-1 did not inhibit NF-kappaB activation, conversion of SIN-1 to a pure NO donor (by addition of excess superoxide dismutase) resulted in potent inhibition of NF-kappaB activation. Dose-response analyses suggest that the inhibitory effect of NO on iNOS gene transcription results specifically from inhibition of NF-kappaB activation, and is mediated by a G-cyclase-independent mechanism that is unavailable to ONOO-. LPS stimulates IkappaB-alpha phosphorylation by inducing IkappaB kinase (IKK) activity, and NO, but not ONOO-, inhibits LPS-induced IkappaB-alpha phosphorylation and IKK activity. CONCLUSION: We demonstrate that only NO inhibits the activation of NF-kappaB and suppresses iNOS gene expression. This distinction provides a novel paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO.

Animals↗