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PubMed2002

Bimoclomol elevates heat shock protein 70 and cytoprotects rat neonatal cardiomyocytes.

Bimoclomol is a new compound that improves cell survival under experimental stress conditions partly by increasing intracellular heat shock proteins (HSPs). HSPs, especially HSP70, play a cytoprotective role in the rat heart. Rat neonatal cardiomyocytes were used to determine the ability of bimoclomol to induce HSP70 and affect cell survival across a broad concentration range (0.01-100 microM). Bimoclomol significantly elevated HSP70 levels at concentrations ranging from 0.01 to 10 microM, depending on the time of exposure. Pretreatment with bimoclomol for 24 h significantly increased survival of cells. There was a significant correlation between the increased levels of HSP70 and the increase in cell survival as a result of the treatment with bimoclomol. In conclusion, bimoclomol improved cell survival in rat neonatal cardiomyocytes, in part, by increasing the levels of HSP70. This cytoprotection began at the relatively low concentration of 0.1 microM, which is a concentration that can be achieved clinically.

Animals↗
PubMed1997

DY-9760e, a novel calmodulin antagonist with cytoprotective action.

We report the pharmacological characterization and cytoprotective effect of DY-9760e, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-( 4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, a novel antagonist of calmodulin. DY-9760e inhibited calmodulin-dependent enzymes, including calmodulin-dependent protein kinase II and IV, calcineurin, [corrected] calmodulin-dependent phosphodiesterase and myosin light chain kinase with Ki values of 1.4, 12, 2.0, 3.8 and 133 microM, respectively. These antagonistic effects of DY-9760e were more potent than those of W-7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, another calmodulin antagonist. This compound showed little or no effect on calmodulin-independent enzymes, such as protein kinase A and C and calpain I and II. Analysis of the hydrophobic interaction of DY-9760e with calmodulin by using 2-p-toluidinylnaphthalene-6-sulfonate and 9-anthroylcholine revealed that, like W-7, DY-9760e bound to the hydrophobic regions of calmodulin. The [14C]DY-9760e binding assay indicated that DY-9760e bound to calmodulin at one class of binding site. Finally, DY-9760e substantially protected N1E-115 neuroblastoma cells from cytotoxicity induced by the Ca2+ ionophore, A23187. These results indicate that DY-9760e, a novel calmodulin antagonist, possesses a cytoprotective action and suggest that calmodulin plays a critical role in mediating some of the biochemical events leading to cell death following Ca2+ overload.

Calcimycin↗
PubMed1986

Cytoprotection by a synthetic prostaglandin against ethanol-induced gastric mucosal damage. A double-blind endoscopic study in human subjects.

This randomized, double-blind, placebo-controlled study compared the cytoprotective effects of misoprostol, a synthetic analog of prostaglandin E1, and cimetidine on ethanol-induced gastric mucosal damage. Forty-five healthy male subjects were accepted, following endoscopy to exclude those with upper gastrointestinal disease. Injury to the gastric mucosa was induced by spraying it with 80% ethanol solution. Misoprostol (200 micrograms) intragastrically or cimetidine (300 mg) orally or placebo was administrated before the ethanol challenge. The gastric mucosa was graded using a seven-point endoscopic scale by two endoscopists 15 and 30 min after ethanol instillation. Thirty minutes following the instillation of ethanol, the gastric mucosa of placebo-treated subjects showed marked damage, with an endoscopic score (mean +/- standard deviation) of 5.5 +/- 0.9. Cimetidine partially prevented gastric mucosal damage, with an endoscopic score of 4.5 +/- 1.7 as compared to placebo (p = 0.04). Misoprostol significantly prevented gastric mucosal injury with a mean endoscopic score of 1 +/- 1.7 when compared to placebo (p = 0.0001) and to cimetidine (p = 0.0002). This cytoprotective action of misoprostol may prove to be clinically very important and warrants further investigation.

Adult↗
PubMed1987

Cytoprotective agents in experimental small bowel volvulus.

An accepted experimental model for midgut volvulus was used to produce small bowel strangulation obstruction of 48 hours duration in Sprague-Dawley rats. A 93% perioperative mortality rate resulted after release of the volvulus. Treatment with three cytoprotective agents at the time of volvulus release resulted in the following mortality rates: superoxide dismutase, 89%; ibuprofen, 50%; prostaglandin E1 (PGE1, 11%. The predominant cause of death in all treatment groups was bowel infarction, with a smaller number succumbing to either sepsis or circulatory collapse. Concomitant administration of ephedrine or indomethacin to suppress prostaglandin E1's splanchnic vasodilatory activity did not cause any increase in mortality. A trial of aspirin, to simulate PGE's antiplatelet actions, showed no reduction in mortality when compared with detorsion alone. Prostaglandin E1 and, to a lesser extent, ibuprofen, appear to have cytoprotective effects during reperfusion of bowel compromised by volvulus, independent of their influence on the mesenteric vasculature and thrombogenesis.

Alprostadil↗
PubMed1991

Cytoprotection and stress ulceration.

The stomach possesses many mechanisms for protection against stress ulceration. The gastric microcirculation, prostaglandins, mucus secretion, epithelial cell renewal, and muscle tone are factors involved in gastric cytoprotection. Therapy is partially directed at augmenting these natural physiologic defense mechanisms to prevent and promote healing of stress ulceration. Drugs such as sucralfate, carbenoxalone, colloidal bismuth, and prostaglandins are used. Stress ulceration is an important cause of upper gastrointestinal tract hemorrhage in postoperative and critically ill patients in the intensive care unit setting. Preventive therapy includes neutralization of gastric acid by antacids, suppression of gastric acid secretion by H2-receptor blockers, administration of cytoprotective agents, and correction of the underlying stress state. Active bleeding requires accurate diagnosis by gastroscopy. Additional therapy may be necessary, including intra-arterial administration of vasopressin and occasionally surgery. Dieulafoy's lesion is an unusual stress-related cause for upper gastrointestinal bleeding. The area of mucosal injury is minute but underneath lies a large submucosal gastric artery. It can cause massive bleeding and is often missed at initial gastroscopy. The pathogenesis of Dieulafoy's lesion is complex and the mainstay of therapy has been surgical. Ligation of the vessel, wedge resection, or proximal gastric resection is performed. Therapeutic endoscopy with endoscopic cauterization or injection has changed the approach to this lesion.

Bismuth↗
PubMed1985

The cytoprotective effect of prostaglandin E2 on taurocholate-induced erosions in gastric mucosa of the rat. Light microscopic, morphometric and scanning electron microscopic investigations.

The morphological changes associated with the cytoprotective effect of prostaglandin E2 (PGE2) following sodium-taurocholate (NaTC) erosive injury in the gastric mucosa were investigated in male rats. A single topic application of NaTC (80 mMol) induced multiple gastric erosions in all animals. Application of 200 micrograms PGE2/kg body weight prior to NaTC treatment led to a significant 90% decrease in the lesion-score in PGE2-protected animals. Light microscopic morphometric studies of the mucus-producing cells in the fundus mucosa were carried out. Within the PGE2-protected animals a significant increase was observed in the length of zones of the mucus-producing cells at the surface and in the foveolae (both PAS-positive and alcian-blue-positive cells). Compared to the NaTC-injured animals, this increase amounted to 8.1% for the PAS-positive, and 6.1% for the alcian-blue-positive zone. Compared to the untreated controls, these values were 4.7% and 3.2% respectively. In the scanning electron microscope we observed a characteristic explosive release of mucus and damage of the cell's surface membranes in the NaTC-treated animals. The PGE2-protected rats showed a predominance of exocytosis of mucus vesicles which formed a characteristic mucus network at the surface membrane. Our investigations suggest that the cytoprotective effect of PGE2 may, in part, be due to an increase in mucus production and to a modification of mucus adherence at the cell membrane.

Animals↗
PubMed2001

Cytoprotective role of Solanum nigrum against gentamicin-induced kidney cell (Vero cells) damage in vitro.

The 50% ethanol extract of the whole plant of Solanum nigrum was tested in vitro for its cytoprotection against gentamicin-induced toxicity on Vero cells. Cytotoxicity was significantly inhibited as assessed by the Trypan blue exclusion assay and mitochondrial dehydrogenase activity (MTT) assay. The test extract also exhibited significant hydroxyl radical scavenging potential, thus suggesting its probable mechanism of cytoprotection.

Animals↗
PubMed2000

Gastric cytoprotection of bolivian medicinal plants.

Several extracts obtained from Bolivian medicinal plants have been evaluated for cytoprotective activity on ethanol-induced ulcer formation in rats. Preliminary results suggest, that the majority of the plants tested showed a significant activity, the aqueous extracts of Phoradendron crassifolium and Franseria artemisioides being the most active, exerting a cytoprotective activity comparable to atropine. The analysis of the chemical constituents of the extracts studied showed the presence of tanins, saponins, flavonoids and coumarins.

Animals↗
PubMed1996

The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine (Ethyol).

Administered prior to cytotoxic chemotherapy or radiation, the aminothiol amifostine provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumour response. The basis for the selectivity of action resides in the anabolism of amifostine at the normal tissue site by membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol, WR-1065, is followed by rapid uptake into normal tissues by a carrier mediated, facilitated diffusion process; in contrast, uptake into tumour tissue is slow to negligible. Preclinical studies have shown that pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes and radiation. Normal tissues protected include bone marrow, kidney, neural tissues, the heart, intestinal crypt cells and pulmonary tissues. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. With respect to bone marrow, preclinical studies have shown significant protection of progenitor cells that give rise to the red and white cells and platelets. Comparative in vitro and in vivo studies using murine and human tumour xenografts show no decrease of antitumour effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as a model for the clinical development programme for this important new broad-spectrum cytoprotective agent.

Amifostine↗
PubMed1995

Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-induced cytoprotection in rats.

The effect of intragastric (i.g.) capsaicin on experimental gastric ulcer was studied in the 1 h pylorus-ligated rats. Capsaicin applied in 40 ng ml-1 concentration (0.1 microgram kg-1) protected against gastric mucosal injury evoked by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. After a capsaicin concentration of 400 micrograms ml-1 (1 mg kg-1) protection occurred initially, while several hours later mucosal damage evoked by acidified aspirin was enhanced. Capsaicin in 2 and 6 ml kg-1 (10 and 30 mg kg-1) invariably aggravated the aspirin and ethanol-induced gastric mucosal damage. Capsaicin in 0.1 microgram kg-1 did not modify the mucosal protective action of prostacyclin (5 micrograms kg-1) on gastric mucosal injury produced by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. Local capsaicin desensitization induced by application of capsaicin in 2 mg ml-1 (10 mg kg-1) did not interfere with the mucosal cytoprotective effects of prostacyclin against ethanol and aspirin-induced mucosal damage. It is concluded that i.g. capsaicin exerts a dual dose-dependent effect on development of experimental gastric ulcer. Neither i.g. capsaicin in small doses nor local capsaicin desensitization modify the mucosal cytoprotective effects of prostacyclin.

Administration, Oral↗
PubMed2003

Oral candidiasis in head and neck cancer patients receiving radiotherapy with amifostine cytoprotection.

This controlled study assessed the incidence of oral candidiasis, a xerostomia-related complication, in head and neck cancer patients receiving radiotherapy, with amifostine cytoprotection. Thirty-eight patients received 500 mg amifostine i.v., prior to each radiotherapy fraction, while 16 patients received radiotherapy alone. Oral candidiasis was diagnosed according to the criteria described before. Subjective xerostomia scales were completed by all patients. Mucositis was evaluated using the RTOG criteria. Oral candidiasis was diagnosed in 11/38 amifostine patients and in 9/16 controls (P = 0.07). Severe xerostomia was reported by 4/38 amifostine patients and by 7/16 controls. Oral candidiasis was reduced with amifostine cytoprotection. Oral candidiasis is suggested as an objective, early, though indirect, endpoint for amifostine's radioprotective effect on salivary glands.

Amifostine↗
PubMed1993

Benzylamine antioxidants: relationship between structure, peroxyl radical scavenging, lipid peroxidation inhibition, and cytoprotection.

Three homologous series of 3,5-dialkoxy-4-hydroxybenzylamines were prepared and tested (1) as peroxyl radical scavengers in homogeneous aqueous solution, (2) as inhibitors of iron-dependent peroxidation of rabbit brain vesicular membrane lipids, and (3) as cytoprotective agents using primary cultures of rat hippocampal neurons exposed to hydrogen peroxide. The structural requirements for efficient radical trapping in homogeneous solution differed from those for effective lipid peroxidation inhibition: In homogeneous solution a kinetic preference existed for smaller, less sterically encumbered substituents flanking the reactive phenolic hydroxyl group. Lipid peroxidation inhibition, on the other hand, required longer more lipophilic substituents. Consequently, a lipophilic alkoxyl substituent at C3 and a small substituent at C5 appeared optimal for efficient radical scavenging activity in both lipid and homogeneous solution. Maximal cytoprotection of rat hippocampal neurons exposed to hydrogen peroxide was also associated with more lipophilic derivatives although substituent length and substituent bulk may represent independent parameters for relating structure and efficacy in this system.

Animals↗
PubMed1992

Antiallergic and cytoprotective activity of new N-phenylbenzamido acid derivatives.

A series of new N-phenylbenzamido acid derivatives was synthesized and evaluated for their ability to inhibit the IgE-mediated passive cutaneous anaphylaxis in the rat (PCA), as well as for their capacity to inhibit gastric mucosal damage induced by the oral administration of absolute alcohol in the rat. Some of these new derivatives exhibit potent antiallergic and cytoprotective activity, 20-80 times higher than that of the reference, disodium cromoglycate (DSCG). Structure-activity relationships are discussed. The antiallergic activity of one of the more potent compounds of this series, i.e. 4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]benzamide (compound 44, CR 2039) was further evaluated in vivo. This compound antagonizes the bronchoconstriction induced by aerosolized ovalbumin in both anesthetized and conscious IgE sensitized guinea pigs with ID50 of 3.7 mg/animal (tracheal insufflation) and 20 mg/kg (im). Further cytoprotective effects were evaluated in gastric ulcer models induced by the acute oral administration of hypertonic sodium chloride solution or by acetic acid and by the subchronic administration of glucose in fasted animals. In the models used experimentally CR 2039 is effective, whereas DSCG seems to be devoid of any protective activity. Such a potent antiallergic and mucosal protectant could provide a new potential agent in the therapy of atopic allergic diseases.

Animals↗
PubMed2002

In vitro lead-induced cell toxicity and cytoprotective activity of fetal calf serum in human fibroblasts.

The underlying mechanisms by which lead ions produce their deleterious effects prior to the onset of clinical symptoms are incompletely understood. This study aimed to assess lead-induced cell toxicity mechanisms by focusing on the effects of the metal on cell growth, DNA synthesis, cellular ATP, intracellular hexosaminidase activity and lysosomal function, and examine the possible cytoprotective role of fetal calf serum (FCS). Several human dermal cultured fibroblast lines were exposed to Pb (400 microM) for 1-6 days with 2, 5, and 10% FCS. The earliest toxic effect of Pb was significant inhibition of DNA synthesis after 24 h direct exposure; this harmful effect was not progressive during the first 3 days, but worsened clearly on the 4th day regardless of the FCS concentration. Atime-dependent depletion of intracellularATP content was also caused by ionic lead, thereby compromising the cell energy charge which precedes cell death. Fibroblast growth was progressively and significantly inhibited from day 2 onwards; the greatest noxious effect was observed in the presence of 2% FCS: 49% reduction in cell proliferation after 5 days. Lead salts produced loss of cell adhesion to the culture dish which worsened from the 2nd day and was more pronounced when FCS in growth medium was decreased. Toxic actions on lysosomal membrane integrity provoked a decrease in neutral red uptake (NRU) which was exposure time-dependent and more marked with 2% FCS. In contrast, increased relative NRU (to 20% at 4 days), suggestive of endocytosis-induced lysosome enlargement, was observed in Pb-exposed cells. Intracellular hexosaminidase activity was not negatively affected until 5 days after exposure to Pb salts. FCS had a significant cytoprotective effect on Pb-induced toxicity.

Adenosine Triphosphate↗
PubMed1993

Utilization of a human intestinal epithelial cell culture system (Caco-2) for evaluating cytoprotective agents.

Human intestinal epithelial cells (Caco-2) were cultured as confluent monolayers on polycarbonate membranes in Transwells for investigating their applicability in evaluating the cytoprotective activity of sucralfate. The control experiments established a reproducible chemical method (using 0.5 mM indomethacin in Hanks' balanced salt solution) for inducing damage to the Caco-2 cell monolayers. Damage was determined by measuring changes in transepithelial electrical resistance (TEER). Twenty-day-old Caco-2 cell monolayers were significantly and reproducibly damaged (compared to buffer alone) (P < 0.001) by application of 0.5 mM indomethacin to the apical side for 1 hr. While sucralfate, at a 0.5, 2, or 5 mg/mL concentration in the buffer, was shown not to reverse (treat) the damage caused by indomethacin in this cellular model, it was able to protect (prevent) the cells from indomethacin-induced damage (P < 0.001). We observed that indomethacin-induced damage to the Caco-2 cell monolayers greatly affected the paracellular pathway since the percentage transport of [3H]methoxyinulin was significantly elevated. In contrast, protection of the Caco-2 cells with 5 mg/mL sucralfate in the presence of the damaging agent resulted in transport of the paracellular marker similar to that in the control (HBSS-treated) cell monolayers. This direct cytoprotective effect was thus independent of vascular factors at neutral pH and was observed to be dose dependent (0.5 to 5 mg/mL) when sucralfate was applied to the cells in the presence of the damaging agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗
PubMed2003

Unique inhibition of bile salt-induced apoptosis by lecithins and cytoprotective bile salts in immortalized mouse cholangiocytes.

Bile duct epithelium is physiologically exposed to high concentrations of bile salts, suggesting the presence of a cytoprotective mechanism(s). The aim of this study was to clarify whether bile salts cause bile duct cell damage and to elucidate the mechanism(s) providing protection against such an action of bile salts. Immortalized mouse cholangiocytes were incubated with taurocholate, taurochenodeoxycholate, glycochenodeoxycholate (GCDC), taurodeoxycholate, and tauroursodeoxycholate (TUDC), followed by flow-cytometric analysis and caspase activity assay to evaluate the induction of apoptosis. GCDC time-dependently induced caspase 3 (3.4-fold)- and caspase 9 (1.4-fold)-mediated apoptosis of cholangiocytes, but this was inhibited by lecithins and TUDC. Further, expression of cholangiocyte bile salt transporters (apical sodium-dependent bile salt transporter [Asbt] and multidrug resistance protein 3 [Mrp3]) was examined by RT-PCR and western blotting, and cholangiocyte bile salt uptake was determined using radiolabeled bile salts. Expression of cholangiocyte Asbt and Mrp3 was increased by bile salts, whereas lecithins interestingly reduced bile salt uptake to inhibit cholangiocyte apoptosis. In conclusion, bile salts themselves cause cholangiocyte apoptosis when absorbed by and retained inside the cell, but this is inhibited by washing out cytotoxic bile salts according to Mrp3, a rescue exporting molecule. Biliary lecithin is seemingly another cytoprotective player against cytotoxic bile salts, reducing their uptake, and this is associated with a reduced expression of Mrp3.

Animals↗
PubMed2003

Cytoprotective and antiapoptotic effects of IL-13 in hepatic cold ischemia/reperfusion injury are heme oxygenase-1 dependent.

Liver injury caused by ischemia/reperfusion (I/R) insult represents the major problem following orthotopic liver transplantation (OLT). I/R damage has been linked to Th1-like cytokine producers. This study evaluates putative cytoprotective effects/mechanisms of Th2-type IL-13 gene transfer. IL-13 overexpression prevented hepatic insult in a rat model of 24 h cold ischemia followed by OLT, as assessed: (i) profoundly decreased hepatocellular damage (sGOT levels), and ameliorated histological signs of I/R injury (Suzuki criteria), consistent with long-term OLT survival; (ii) prevented hepatic apoptosis (TUNEL stains) and up-regulated expression of antiapoptotic (A20, Bcl-2/Bcl-xl)/antioxidant (HO-1) genes. However, inhibition of HO-1 with tin protoporphyrin reversed cytoprotective/antiapoptotic effects of IL-13. In conclusion, cytoprotection rendered by virally induced IL-13 against hepatic I/R injury in this clinically relevant rat hepatic cold I/R injury model was accomplished via decreased apoptosis and induction of antiapoptotic/antioxidant molecules. HO-1 neutralization studies suggest that HO-1 represents one of putative IL-13 downstream effectors. This study provides the rationale for novel approaches to maximize organ donor pool through the safer use of OLTs despite prolonged periods of cold ischemia.

Animals↗
PubMed1992

A mechanism of glycine and alanine cytoprotective action: stimulation of stress-induced HSP70 mRNA.

Studies done both in vitro and in vivo have shown that glycine and alanine protect kidney cells from stress injury. However, the mechanism(s) of this cytoprotection is unknown. Our aim was to test the hypothesis that the cytoprotective action is in part due to stimulation of gene(s) expression encoding stress protein synthesis. Experiments were carried out using heat shock as a model for stress in the opossum kidney cell line (OK cells). The induction of HSP70 mRNA was evaluated in cell monolayers exposed to 45 degrees C for 15 minutes followed by a recovery period at 37 degrees C for either 0.5, 1, 2, 3, 4, 6 or 24 hours. The results demonstrate that the maximum level of HSP70 mRNA occurred at approximately three hours after heat treatment. Although the mRNA levels declined thereafter, appreciable amounts were still seen even 24 hours after heat-shock. To examine the effect of glycine or alanine on HSP70 mRNA levels and on the synthesis of stress protein, cultures were preincubated for 30 minutes with Krebs-Henseleit buffer, pH 7.4, supplemented with either 1, 2, 5 or 10 mM glycine or alanine, or with no added amino acids. Comparative studies were performed with 10 mM glutamate, aspartate, arginine or leucine. Following preincubation, cultures were heat-shocked (45 degrees C for 15 min) and then reincubated at 37 degrees C for three hours. Both glycine and alanine enhanced the level of HSP70 mRNA and the synthesis of 72, 73 kDa stress proteins, but neither amino acid induced HSP70 mRNA without concomitant heat treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗