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PubMed1985

Structural requirements for cytoprotective agents in galactosamine-induced hepatic necrosis.

A variety of compounds were tested for their ability to inhibit the development of galactosamine-induced hepatic necrosis when administered 12 hr after the toxicant. Hepatic necrosis in male Sprague-Dawley rats was quantified by histopathologic examination 24 hr after a hepatotoxic dose of D(+)-galactosamine HCl (400 mg/kg, ip). Compounds found to have antinecrotic activity were not able to eliminate the accumulation of calcium associated with galactosamine-induced hepatic necrosis. Potent calcium chelators (EDTA and EGTA), compounds with aminoethanethiol-chelating structures (cysteamine and penicillamine), compounds that may be metabolized to aminoethanethiol structures in vivo (N-acetylcysteine, 2-aminoethylisothiourea, and cystamine), and a compound known to alter subcellular calcium sequestration (taurine) all inhibited galactosamine-induced hepatic necrosis. Compounds without antinecrotic effects (S-methylcysteamine, thioproline, dimercaptopropanesulfonic acid, and dimercaptosuccinic acid) do not possess structural or functional characteristics of the antinecrotic agents. It is suggested that chelation of free intercellular calcium or enhanced subcellular sequestration of calcium could explain the reduction of cytotoxic consequences of hepatic calcium accumulation observed in this model.

Animals↗
PubMed1996

Cytoprotective activity of cisapride on experimental gastric mucosal lesions induced by ethanol. Role of endogenous prostaglandins.

The antiulcer effects and protective mechanisms of cisapride, a prokinetic benzamide agonist of 5-HT3 and antagonist of 5-HT4 receptors, were investigated in gastric mucosal injury induced by pretreatment with 50% v/v ethanol in rats. The duration of the protective effect was also studied and the results were compared with those of 5-HT. 240 min after administration of cisapride (10, 25 and 50 mg/kg) the total area of gastric lesions decreased significantly, in macroscopical and histological evaluations, and the mucus, hexosamine, and sulphated glycoprotein content were significantly increased. Indomethacin partially reversed cisapride protection suggesting that the beneficial antiulcer effects of this drug could be mediated in part by prostaglandins. This study confirms that this benzamide, in this experimental model, enhances gastric PGE2 production. We also investigated the time course of action of 5-HT, 30-240 min before ethanol administration, and our study not only demonstrates the ulcerogenic action of the amine (30 min of pretreatment) but also its protective nature, shown macroscopic and microscopically, after 240 min of its administration, without any effect on PGs production. These findings suggest a new gastroprotective feature of cisapride partly explained through a prostaglandin-dependent mechanism and possibly independent of its 5-HT activity.

Animals↗
PubMed1984

Cytoprotective and antisecretory effects of 11-deoxy-13,14-didehydro-16(s)-methyl PGE2 methylester (FCE 20700).

A new, chemically stable analogue of PGE2, 11-deoxy-13,14-didehydro-16(S)-methyl PGE2 methylester (FCE 20700) was studied for the prevention of different gastrointestinal ulcers and for the inhibition of basal gastric acid secretion in the rat. The diarrhoea-inducing activity was also investigated. FCE 20700 was more potent than PGE2 in the prevention of stress-induced gastric ulcers (ED50 = 262 and 787 mcg/kg) and indomethacin-induced intestinal ulcers (ED50 = 557 and 4569 mcg/kg), and showed the same potency as PGE2 in the prevention of ethanol (ED50 = 9.2 and 14.8 mcg/kg) and indomethacin-induced gastric ulcers (ED50 = 37.8 and 22.3 mcg/kg). FCE 20700 weakly affects gastric acid secretion with an ED50 of 2385 mcg/kg, showing clear separation of antisecretory activity and gastric antiulcer potency. FCE 20700 does not induce diarrhoea in rats at doses up to 6.25 mg/kg, 10 to 600 times the effective antiulcer doses.

Animals↗
PubMed1987

Cytoprotective effects of modulators of oxidative xenobiotic metabolism in precocene II-induced hepatotoxicity.

This investigation was conducted to evaluate the effects of modulation of several phase I xenobiotic-metabolizing enzyme activities on the expression of precocene II-induced hepatotoxicity. Precocene II (175-200 mg/kg) was given intraperitoneally to male Sprague-Dawley rats that had been exposed previously to inducers (phenobarbital and 3-methylcholanthrene) or inhibitors (SKF 525-A and cimetidine) of oxidative xenobiotic metabolism. Hepatic damage was measured both biochemically (leakage of aspartate aminotransferase and alanine amino-transferase into the serum) and histologically. Significant protection from precocene II-induced hepatotoxicity was observed in all treated animals regardless of whether the modulator employed was an inducer or an inhibitor of microsomal oxidative enzymes. These results indicate that the level of activity of various forms of cytochrome P-450 significantly influences the severity of hepatic necrosis induced by precocene II. Furthermore, these results suggest that inducible non-P-450 factors, such as glutathione S-transferases, may be important in modulating precocene II-induced hepatotoxicity.

Alanine Transaminase↗
PubMed1995

The cytoprotective roles of ascorbate and glutathione against nitrogen dioxide toxicity in human endothelial cells.

The depletion of human umbilical vein endothelial (HUVE) cell glutathione with buthionine sulfoximine or with sulfur amino acid-free medium potentiated the sub-lethal (3H-deoxyglucose release) and lethal (lactate dehydrogenase release) cytotoxicity responses of the cells to direct exposure to NO2 over the range 2-20 ppm. When control cells, or glutathione-depleted cells, were either pre-loaded with ascorbate (intracellular ascorbate), or washed with ascorbate-containing medium just before exposure (extracellular ascorbate), the cells were fully protected from NO2-dependent toxicity. Concomitant with these exposures, NO2 caused dose-dependent depletions of both glutathione and ascorbate. Further, it was noted that the depletion of the intracellular ascorbate pool was accelerated in these glutathione depleted cells. Conversely, loading ascorbate into the cells significantly diminished NO2-dependent depletion of intracellular GSH. In contrast to affecting the acute cytotoxicity response of the HUVE cells to NO2, ascorbate supplementation of the medium of cells exposed to NO2 at clonal density facilitated considerable protection to the colony-forming efficiency of the cells. We conclude that both ascorbate and glutathione play important protective roles in defending HUVE cells from the toxicity of NO2 under direct exposure conditions. The results also strengthen the premise that ascorbate and glutathione co-operate in the antioxidative protection of cellular viability.

Antioxidants↗
PubMed1994

The role of gastric muscle relaxation in cytoprotection induced by san-huang-xie-xin-tang in rats.

We examined the mechanism of the protective effect of San-huang-xie-xin-tang (SHXT), a traditional oriental drug, on the gastric mucosa. SHXT, given intraduodenally, inhibited the gastric secretion in pylorus-ligated rats. SHXT, given orally 30 min before the administration of aspirin, HCl-aspirin and ethanol, protected the gastric mucosa from these agent-induced gastric lesions, although it had no effect on the gastric lesions induced by indomethacin and water immersion stress. Oral administration of SHXT increased gastric contents (muscle relaxation) when they were measured 30 min after SHXT administration. SHXT also inhibited carbachol-contracted gastric muscle in vitro. Neither increased gastric contents nor inhibited ethanol lesions of SHXT were observed when these were tested 4 h after SHXT administration. Pretreatment with indomethacin which is a prostaglandin synthesis inhibitor, and N-ethylmaleimide which is a sulfhydryl blocker did not influence either the increased gastric contents or inhibited ethanol lesions of SHXT. These results indicate that gastric muscle relaxation plays an important role in the gastric protective mechanisms of SHXT, and the endogenous prostaglandins and the sulfhydryl compounds are not necessary for the action of SHXT.

Administration, Oral↗
PubMed1993

Cytoprotective effect of NMDA receptor antagonists on prion protein (PrionSc)-induced toxicity in rat cortical cell cultures.

Rat cortical cells were incubated with the Scrapie prion protein, PrionSc. At concentrations of 3 ng/ml of PrionSc and higher, the viability of the cells decreased significantly after a 12-h incubation period. Simultaneously, the degree of DNA fragmentation increased. In control experiments with antibodies against PrionSc, PrionSc lost its deleterious effect on neurons. PrionSc did not affect the viability of astrocytes. Drugs known to block NMDA receptor channels, such as memantine (1-amino-3,5-dimethyl-adamantane) (Mem), its analogue 1-N-methylamino-3,5-dimethyl-adamantane as well as (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) prevented the effect of PrionSc. Production of PrionSc in the Scrapie prion-infected subclone of N2 a cells (ScN2 a cells) was not affected by memantine. We conclude that antagonists of the NMDA receptor-channel complex (i) abolish the PrionSc-induced neuronal injury in vitro, and (ii) display no influence on the synthesis and/or the processing of PrionSc.

Animals↗
PubMed1991

Mechanism(s) of cytoprotective and anti-inflammatory activity of PGB1 oligomers: PGBx has potent anti-phospholipase A2 and anti-oxidant activity.

We postulate that the anti-PLA2 and anti-oxidant activities may account for the broad spectrum protective effects of PGBx that were previously described. These dual properties are demonstrable in vitro, in situ and in vivo, and would have profound effects on stabilization of membrane structure and function, which in turn, would protect organelles, cells, tissues, and organs from inflammation and injury, and possibly alter patterns of aging involving senescence and cell death.

Animals↗
PubMed2005

Failure of FK506 (tacrolimus) to alleviate apomorphine-induced circling in rat Parkinson model in spite of some cytoprotective effects in SH-SY5Y dopaminergic cells.

The mechanism of action of the neurotoxin 6-hydroxydopamine (6-OHDA) is thought to involve the generation of free radicals and subsequent apoptotic processes. We have demonstrated in vitro that the neuroimmunophilin, FK506 (10-100 nM), dose dependently and significantly restored the ROS production to the control level, increased the Bcl-2 protein level, partly inhibited the cytochrome C release from mitochondria and reduced the caspase-3 activation in SH-SY5Y cells. On the other hand, there was no significant restoration of the ATP level by FK506 and the toxin activated proteins, p53 and Bax, were not normalized by FK506. In support of these latter results, daily administration of FK506 for 7 days to rats (0.5, 1 and 3 mg/kg i.p.) did not significantly prevent the apomorphine-induced contralateral circling, measured 2 weeks after unilateral nigral lesioning. Moreover, FK506 pretreatment did not significantly lower the toxin elevated lipid peroxidation levels, indicating that oxidative stress was present even after the FK506 treatment in the lesioned striatum. Taken together, our results with FK506 are inconsistent. We confirm the antioxidant nature of FK506, that is, it blocks ROS production in SH-SY5Y cells. However, there were no significant protective effects in any apoptotic analyses in SH-SY5Y cells and in animal studies, a 7-day FK506 pre-treatment was not able to reverse the toxic effect of 6-OHDA in a rat model of Parkinson's disease.

Animals↗
PubMed2003

The cytoprotective role of a low-molecular-weight heparin fragment studied in an experimental model of glomerulotoxicity.

Abnormal glomerular glycosaminoglycan metabolism is involved in the onset of the morphological and functional aberrations of glomerulopathies. In the present study, a heparin derivative, low-molecular-weight heparin, was tested for its ability to afford renoprotection in an established model of experimental glomerulopathy. Two groups of male albino rats of the Wistar strain (140 +/- 10 g) received a single intravenous injection of adriamycin (7.5 mg/kg) to induce glomerulopathy, and one of them received low-molecular-weight heparin (Certoparin Sodium, Troparin; 300 microg/day/rat s.c.) treatment, commencing on day 8, for a week. Urinary protein/creatinine ratio, serum albumin, urea, uric acid and creatinine clearance were evaluated. Renal cell injury was assessed in terms of renal tissue lactate dehydrogenase, aminotransferases (aspartate and alanine transaminases) and alkaline phosphatase activities, as well as renal antioxidant status (superoxide dismutase, catalase and glutathione peroxidase, reduced glutathione, vitamins E and C). The kidney tissue was subjected to histopathologic examination. Low-molecular-weight heparin significantly reduced proteinuria and improved creatinine clearance and serum albumin levels in the rats with glomerulopathy. The significant rise in serum uric acid in the rats with glomerulopathy was reversed by low-molecular-weight heparin. Altered tissue enzyme activities in response to injury, oxidative stress challenged renal antioxidant system and abnormal renal histology were observed in the untreated nephrotic rats, while low-molecular-weight heparin treatment protected the nephrotic rats against these changes. Thus, in this study, low-molecular-weight heparin was evaluated for its role in combating glomerular injury, on the basis of some salient biochemical parameters, oxidative injury indices and histologic picture. The ability of low-molecular-weight heparin to restore glomerular anatamo-functional features in this nephrotoxic condition illuminates its multi-faceted renoprotective role.

Animals↗
PubMed2005

Cytoprotective effect of tectorigenin, a metabolite formed by transformation of tectoridin by intestinal microflora, on oxidative stress induced by hydrogen peroxide.

In the present study, the antioxidative properties of tectorigenin, a metabolite formed by transformation of tectoridin by intestinal microflora, were investigated. Tectorigenin was found to scavenge intracellular reactive oxygen species, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, and thus prevented lipid peroxidation. The radical scavenging activity of tectorigenin protected the viability of Chinese hamster lung fibroblast (V79-4) cells exposed to hydrogen peroxide (H2O2) via activation of extracellular signal regulated kinase (ERK) pathway. Furthermore, tectorigenin reduced the apoptotic cells formation and cell cycle arrest at G2/M phase induced by H2O2. Tectorigenin increased the activities of cellular antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, and also increased their protein level. Taken together, these findings suggest that tectorigenin protected V79-4 cells against H2O2 damage, by enhancing the antioxidative activity and by activating ERK pathway.

Animals↗
PubMed2006

Fe(III) improves antioxidant and cytoprotecting activities of mangiferin.

Iron-induced oxidative stress has been implicated in several pathological processes. In the present work we provide evidence for the formation of a mangiferin:Fe(III) complex (2:1), shown by means of either iron-induced changes in the UV/visible spectrum of mangiferin or by reduction of the anodic current peak in the voltammogram of that compound; we demonstrate, in addition, that the ferric complex is more effective than mangiferin itself in scavenging superoxide radicals generated by pyrogallol autoxidation, as well as in protecting hepatocytes from reactive oxygen species mediated hypoxia/reoxygenation injury. Moreover, we found that the mangiferin:Fe(III) complex reacts more readily with horseradish peroxidase/H(2)O(2) than does mangiferin by itself. We postulate that mangiferin could afford protection against iron/reactive oxygen species-mediated pathological processes by means of both iron chelating and iron-stimulated superoxide radical scavenging activity.

Animals↗
PubMed2004

Potential roles of NF-kappaB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline.

Tetrahydropapaveroline (THP), a dopamine-derived tetrahydroisoquinoline catechol, has been suspected to be dopaminergic neurotoxin that elicits parkinsonism and neurobehavioral abnormalities associated with chronic alcoholism. THP has been detected in the brains of parkinsonian patients, and its urinary as well as brain level increases after l-3,4-dihydroxyphenylalanine treatment. Autoxidation or enzymatic oxidation of THP and subsequent generation of reactive oxygen species (ROS) may contribute to the degeneration of dopaminergic neurons induced by this tetrahydroisoquinoline alkaloid. In the present study, THP was found to elicit cytotoxicity in cultured rat pheochromocytoma (PC12) cells, which was completely blocked by reduced glutathione and N-acetyl-L-cysteine. THP-treated PC12 cells exhibited increased intracellular accumulation of ROS and underwent apoptosis as determined by poly(ADP-ribose)polymerase cleavage, an increased ratio of Bax to BclxL, terminal transferase-mediated dUTP nick end labeling, and nuclear fragmentation or condensation. THP treatment caused activation of the redox-sensitive transcription factor nuclear factor kappaB (NF-kappaB). Pretreatment of PC12 cells with NF-kappaB inhibitors, such as l-1-tosylamido-2-phenylethyl chloromethyl ketone and parthenolide, aggravated THP-induced cell death. THP treatment resulted in differential activation of mitogen-activated protein kinases as well as Akt/protein kinase B, thereby transmitting cell survival or death signals. In conclusion, THP induces apoptosis in PC12 cells by generating ROS. THP-mediated oxidative stress was accompanied by differential activation of intracellular signaling kinases and NF-kappaB.

Animals↗
PubMed2006

Resistance to experimental colitis depends on cytoprotective heat shock proteins in macrophage migration inhibitory factor null mice.

Macrophage migration inhibitory factor plays an important role in inflammatory diseases. We investigated the role of macrophage migration inhibitory factor (MIF) in the development of dextran sulfate sodium (DSS)-induced colitis using MIF null ((-/-)) mice. MIF(-/-) mice given 3% DSS showed no clinical and histological feature of colitis in contrast to wild-type (WT) mice. Lack of MIF suppressed the up-regulation of TNF-alpha and IFN-gamma as Th1-derived cytokines, and increased the level of IL-4 as Th2-derived cytokine in the colon tissues. Moreover, we found that the expressions of heat shock protein (HSP)40 and HSP70 were markedly up-regulated in the colon of MIF(-/-) mice in response to DSS compared with WT mice. Additionally, quercetin, an inhibitor of HSP synthesis, inhibited the up-regulation of HSP40 and 70 expressions and developed DSS-induced colitis in MIF(-/-) mice. Our findings in this study provide more information in the role of MIF in colitis.

Animals↗