Histological study of mechanisms of adaptive cytoprotection on ethanol-induced mucosal damage in rat stomachs

Adaptive cytoprotection in the gastric mucosa could be induced by exposure to low concentrations of noxious agents. However, experimental results reported so far were based on macroscopic studies. We aimed to investigate the phenomenon of gastric adaptive cytoprotection of mild irritants and its correlation with intramucosal mucus at the histological level. It was found that histological damage induced by ethanol had a negative correlation with the length of the mucus-secreting layer in the gastric mucosa. Mild irritants such as 20% ethanol and 5% NaCl preserved the 100% ethanol-induced intramucosal mucus depletion, but only the former agent demonstrated a cytoprotective effect against the histological damage, indicating that preservation of intramucosal mucus may not necessarily play a permissive role in adaptive cytoprotection. The capsaicin-sensitive sensory afferent neurons, sensory chemoreceptors, muscarinic receptors, alpha2-adrenoceptors and peripheral dopamine D2-receptors were found to be the components of the autonomic nervous system involved in the cytoprotective processes of 20% ethanol. Endogenous mediators including nitric oxide, prostaglandins, and possibly nonprotein sulfhydryl compounds also seemed to participate in such protection. Nevertheless, 0.3 M HCl did not show any effect either on mucosal damage or depletion of intramucosal mucus induced by absolute ethanol. These findings suggest that only 20% ethanol shows histological cytoprotection, which would involve various components of the autonomic nervous system and endogenous mediators. Furthermore, this investigation also implies a new perspective: that in order to study a true adaptive cytoprotection, histological examination of the gastric mucosa should be performed.     

A mechanistic study of beta-adrenoceptor antagonists on ethanol-induced gastric damage

BACKGROUND: In the first weeks of life there are important maturational changes in the central nervous system in many species in energy metabolism, synapse number, and concentration of neuronal excitatory receptors. METHODS: Four groups of 10 piglets (aged 1, 2, 4, and 10 weeks) underwent 1 hour of deep hypothermic circulatory arrest at 15 degrees C, with cooling and rewarming on cardiopulmonary bypass. Cerebral blood flow and metabolic rate measurements and electroencephalographic recordings were obtained from 5 animals per group. The remaining animals underwent cerebral magnetic resonance spectroscopy. RESULTS: Preoperative cerebral blood flow and glucose consumption were higher at 4 and 10 weeks than at 1 and 2 weeks. Cerebral adenosine triphosphate content decreased more rapidly during deep hypothermic circulatory arrest at 4 and 10 weeks. Phosphocreatine recovery was greater at 30 minutes of reperfusion at 10 weeks compared with 1 week. Recovery of cerebral phosphocreatine/ adenosine triphosphate ratio and intracellular pH was remarkably uniform at all ages. Latency to recovery of electroencephalographic activity decreased with increasing age (p = 0.04). CONCLUSIONS: Differences in acute recovery of brain energy metabolism and electroencephalogram after cardiopulmonary bypass and 1 hour of deep hypothermic circulatory arrest in piglets between 1 and 10 weeks of age are small. Further studies are required to correlate these acute findings with subsequent neurologic outcome.     

Effects of gastric mucosal blood flow (GMBF) on the role of adaptive cytoprotection of rat gastric mucosa

It has been reported that ingestion of an ammonium-containing diet produces hyperammonemia without encephalopathy, thus permitting the study of the specific effects of ammonia toxicity. The present study investigated the rat cerebral somatostatinergic system using this experimental model of hyperammonemia. Wistar rats were fed a high ammonia diet prepared by mixing a standard diet with ammonium acetate (20% w/w); in addition, 5 mM of ammonium acetate was added to their water supply. Control rats were fed with a standard diet. The animals were sacrificed at 3, 7 and 15 days of ammonia ingestion. Ammonia levels in blood had increased approximately 3-fold at 7 days of ammonia ingestion. These changes were associated with a significant decrease in the specific binding of somatostatin (SS) to putative receptors sites in the frontoparietal cortex and hippocampus at 7 and 15 days after starting the high ammonia diet. Scatchard analysis shows that the decrease in SS binding resulted from a decrease in the number of available SS receptors rather than a change in receptor affinity. No changes in the somatostatin-like immunoreactivity content (SSLI) were detected in either brain area at the three study times. These results suggest that hyperammonemia alone can affect the rat brain somatostatinergic system. However, the animal model of hyperammonemia used here is insufficient to produce encephalopathy despite the significant increase in serum ammonia.     

Effect of tetramethylpyrazine on reserpine-induced gastric lesion in rats

The present study was undertaken to determine the effect of tetramethylpyrazine administered intraperitoneally on gastric lesions, gastric acid secretion, gastric barrier mucus secretion, and gastric contraction in reserpine-treated rats. The results of this study demonstrated that tetramethylpyrazine at doses of 0.5, 1, 10, and 20 mg/kg significantly inhibited the formation of gastric lesions induced by reserpine, with suppressive rates of 57.5%, 64.0%, 94.1%, and 96.0%, respectively. Tetramethylpyrazine (1 and 20 mg/kg) significantly prompted the secretion of gastric barrier mucus but had no effect on the secretion of gastric acid. Our findings also showed that tetramethylpyrazine (1 and 20 mg/kg) significantly suppressed the frequency of gastric contractions, but had no effect on the amplitude of gastric contraction. These results indicate that the protection of tetramethylpyrazine results, in part, from promoting gastric barrier mucus secretion and suppressing the frequency of gastric contraction, but not from suppressing the secretion of gastric acid and the amplitude of gastric contraction.     

Phosphatidylcholines as mediators of adaptive cytoprotection of the rat duodenum

BACKGROUND/AIMS: Surfactant phospholipids impede diffusion of acid through the gastric mucus, but their relevance in the defense of the duodenum against luminal acid is not known. METHODS: Duodenal resistance to acid was tested in anesthetized rats by instillation of HCl using a tube implanted in the proximal duodenum. The effects of a detergent (Brij 35; Sigma, St. Louis, MO) and a lipid mixture flushed through the luminal surface on duodenal resistance to acid were studied. The lipid content in the mucus and the effects of acid, prostaglandins, and indomethacin on the lipid layer were also analyzed. RESULTS: Instillation of 100 mumol HCl or 5 micrograms/kg 16,16-dimethyl prostaglandin E2 increased resistance to acid, preventing duodenal lesions induced by 500 mumol HCl. However, 100 mumol HCl or 16,16-dimethyl prostaglandin E2 did not prevent lesions induced by 500 mumol HCl in rats undergoing perfusions with 5% Brij 35. Indomethacin suppressed acid-induced protection. A mixture of tripalmitin and dipalmitoyl-phosphatidylcholine protected against 500 mumol HCl, and the effect was also observed in rats receiving indomethacin. Finally, 100 mumol HCl increased the phosphatidylcholine content in the duodenal mucus but not in rats receiving 5% Brij 35 or indomethacin. CONCLUSIONS: Surface-active phospholipids are critical for adaptive cytoprotection to acid in the rat duodenum.     

A correlative histofluorescence and light microscopic study of the formation of the sympathetic trunks in chick embryos

The appearance and development of the primary and secondary sympathetic trunks in staged chick embryos was studied using the Falck-Owman histochemical method for the demonstration of primary monoamines. The earliest appearance of catecholamine (stage 20) was in individual fluorescent cells located in the region of the dorsal root ganglia about two stages prior to the formation of primary trunk aggregates. These cells are believed to be sympathetic precursor cells and correspond to formaldehyde-induced fluorescent cells observed in recent explantation experiments. Aggregates of fluorescent cells had formed bilaterally dorsolateral to the aorta at stage 22. These aggregates became continuous to form primary trunks by stage 24. The secondary sympathetic trunks were first seen in stage 25 and appeared to form at least partially by dorsal migration of cells from the primary trunks. Fluorescent cell processes were first observed at this stage. Secondary trunk formation was essentially complete by stage 28, and the primary trunks had become small and discontinuous. Definite rami communicantes could be observed by the early part of stage 28 in silver preparations. The significance of the development of two successive trunks in avians is discussed.     

Involvement of free radicals and histamine in the potentiating action of cigarette smoke exposure on ethanol-induced gastric mucosal damage in rats

Cigarette smoking has been associated with peptic ulcer diseases. We studied the effects of cigarette smoke exposure on ethanol-induced gastric mucosal damage and its relationship with vascular integrity and the possible role of free radicals and histamine. Male Sprague-Dawley rats were exposed to cigarette smoke followed by ethanol administration (70% v/v). Smoke exposure alone dose-dependently reduced basal blood flow and increased xanthine oxidase (XO) activity but superoxide dismutase (SOD) activity remained unaffected in gastric mucosa. Cigarette smoking followed by ethanol administration significantly potentiated mucosal lesion formation along with augmentation of the mucosal blood flow, vascular permeability and myeloperoxidase (MPO) activity. The potentiating effect of smoking on ethanol-induced gastric mucosal lesion and MPO activity was abolished by pretreatment with allopurinol, terfenadine or ranitidine. Terfenadine and ranitidine also reduced the increased mucosal blood flow and vascular permeability induced by smoking and ethanol combined. These findings suggested that cigarette smoke adversely affected the defense mechanisms of the gastric mucosa by reducing the mucosal blood flow which in turn led to ischemia and increased XO activity. Activation of XO together with histamine H1 and H2 receptors stimulation could lead to neutrophil aggregation and vascular damage. However, the potentiating action of cigarette smoke on ethanol ulceration is unlikely through reduction of SOD activity in gastric mucosa.     

Selenoperoxidase-mediated cytoprotection against the damaging effects of tert-butyl hydroperoxide on leukemia cells

Murine leukemia L1210 cells grown for 5-7 d in the presence of 1% serum without added selenium [Se(-) cells] expressed < 5% of the glutathione peroxidase (GPX) activity of selenium-supplemented controls [Se(+) cells]. Clonogenic survival assays indicated that t-butyl hydroperoxide (t-BuOOH) is much more toxic to Se(-) cells (LC50 approximately 10 microM) than to Se(+) or selenium-repleted [Se(-/+)] cells (LC50 approximately 250 microM). Hypersensitivity of Se(-) cells to t-BuOOH was partially reversed by treating them with Ebselen, a selenoperoxidase mimetic; thus, selenoperoxidase insufficiency was probably the most serious defect of Se deprivation. Cytotoxicity of t-BuOOH was inhibited by desferrioxamine and by alpha-tocopherol, indicating that redox iron and free radical intermediates are involved. Elevated sensitivity of Se(-) cells to t-BuOOH was accompanied by an increased susceptibility to free radical lipid peroxidation, which became even more pronounced in cells that had been grown in arachidonate (20:4, n-6) supplemented media. That glutathione (GSH) is required for cytoprotection was established by showing that Se(+) cells are less resistant to t-BuOOH after exposure to buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. Coupled enzymatic assays indicated that Se(+) or Se(-/+) cells metabolize t-BuOOH 20-25 times more rapidly than Se(-), consistent with the measured difference in GPX activities of these cells. Correspondingly, when challenged with t-BuOOH, Se(+) cells showed an initial loss of GSH and elevation of GSSG that exceeded that of Se(-) cells. It was further shown that like Se(-) cells, BSO- or BCNU-treated Se(+) cells metabolize t-BuOOH more slowly than nontreated controls. These results clearly indicate that selenoperoxidase action in the glutathione cycle is a vital element in cellular defense against toxic hydroperoxides.     

Ocimum sanctum Linn--a study on gastric ulceration and gastric secretion in rats

Adenosine has been proposed as a useful diagnostic agent in patients with narrow complex regular tachycardia of uncertain origin. Its effects are usually transient owing to its extremely short plasma half life and, as a consequence, it is thought to be safer than other drugs used in the acute treatment of such arrhythmias. However, adenosine had a proarrhythmic effect when administered to a patient in order to confirm the diagnosis of atrial flutter. As expected, a transient increase in atrioventricular block was seen but this was followed by a doubling of the ventricular rate and haemodynamic compromise requiring immediate DC cardioversion. It is postulated that the secondary catecholamine-mediated effects of adenosine were responsible for this phenomenon.     

The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa

The plant pathogenic isolate RI-64 of anastomosis group 4 of Rhizoctonia solani possesses three linear DNA plasmids (pRS64-1, -2, and -3). Unique poly(A)- RNA, 0.5 kb in length and hybridizable with the pRS64 DNAs was found in mycelial cells of the isolate RI-64. The overall homology at the nucleotide level between pRS64-1, -2, and -3, and the cDNA prepared from the poly(A)- RNA was 100%, 73%, and 84%, respectively. The open reading frames found in pRS64-1, -2, and -3 (ORF1-1, ORF2-1, and ORF3-1) are 68 amino acids long. The amino acids sequence showed no significant homology with known proteins. Extracts from Escherichia coli cells expressing ORF1-1 contain a specific protein of 7 kDa. Antisera raised against the ORF1-1 product obtained from E. coli cells cross-reacted with the specific proteins found in the mycelia. The results indicate that the DNA plasmids found in R. solani contain a sequence that encodes a specific protein which may be involved in determination of plant pathogenicity.     

Central effect of melatonin against stress-induced gastric ulcers in rats

We investigated the role of melatonin in the induction of gastric lesions induced by water immersion restraint stress or centrally administered thyrotropin-releasing hormone (TRH). Melatonin (0.1-1 ng) injected intracisternally (i.c) 30 min prior to stress dose-dependently inhibited the induction of gastric lesions by water immersion restraint stress, while 100 micrograms/kg, i.p. failed to protect the gastric mucosa. Preadministration of melatonin (1 ng, i.c.) significantly reduced (83%) the severity of gastric lesions induced by a TRH analogue (500 ng, i.c.). Serum melatonin concentrations 30 min after administration of 1 ng melatonin i.c. did not differ from those of rats receiving i.c. vehicle. These results suggest that melatonin plays a protective, anti-stress, role in the gastric mucosa via a mechanism involving the central nervous system.     

Mucosal irritation, adaptive cytoprotection, and adaptation to topical ammonia in the rat stomach

BACKGROUND: The urease-ammonia (NH4OH) system has been proposed to play a major role in the pathogenesis of the Helicobacter pylori-associated gastritis, but the mechanism of the mucosal damage has not been fully explained. This study was designed to examine possible adaptive cytoprotection and the adaptation of rat gastric mucosa to the irritant action of NH4OH and urease. METHODS AND RESULTS: Single application of NH4OH alone in various concentrations (15-500 mM) caused concentration-dependent mucosal damage starting with 30 mM and reaching a maximum at 250 mM NH4OH, similar to that obtained with 100% ethanol; it was accompanied by a decrease in gastric blood flow (GBF) to approximately 30% of the normal value. When the mucosa was first exposed to the low, non-damaging concentration (15 mM) of NH4OH and then insulted with 100% ethanol, the extent of ethanol damage was greatly attenuated as compared with that caused by ethanol alone. This adaptive cytoprotection was accompanied by the rise in GBF and reversed, in part, by the pretreatment with indomethacin, an inhibitor of prostaglandin (PG)-cyclooxygenase; with L-NAME, a blocker of NO-synthase; or with capsaicin deactivating the sensory nerves. Damaging concentrations of NH4OH (125 mM) caused widespread mucosal damage after the first application, but with repeated insults with 125 mM NH4OH a gradual reduction in the mucosal lesions, accompanied by enhanced mucosal cell proliferation and over-expression of epidermal growth factor (EGF) (using immunocytochemistry) and mRNA of EGF (using trans-reverse polymerase chain reaction), were observed. CONCLUSIONS: NH4OH alone damages gastric mucosa only at the concentration exceeding that found in H. pylori-infected stomachs, whereas at lower concentrations it acts as 'mild' irritant to induce adaptive cytoprotection. This adaptive cytoprotection appears to be mediated, in part, by endogenous PG, sensory nerves, and an arginine-NO-dependent pathway, and repeated applications of NH4OH induce gastric adaptation, probably mediated by enhanced expression of EGF and its receptors and by an increased cell proliferation.     

Taurine: protective properties against ethanol-induced hepatic steatosis and lipid peroxidation during chronic ethanol consumption in rats

Alcohol was administered chronically to female Sprague Dawley rats in a nutritionally adequate totally liquid diet for 28 days. This resulted in hepatic steatosis and lipid peroxidation. Taurine, when co-administered with alcohol, reduced the hepatic steatosis and completely prevented lipid peroxidation. The protective properties of taurine in preventing fatty liver were also demonstrated histologically. Although alcohol was found not to affect the urinary excretion of taurine (a non-invasive marker of liver damage), levels of serum and liver taurine were markedly raised in animals receiving alcohol + taurine compared to animals given taurine alone. The ethanol-inducible form of cytochrome P-450 (CYP2E1) was significantly induced by alcohol; the activity was significantly lower than controls and barely detectable in animals fed the liquid alcohol diet containing taurine. In addition, alcohol significantly increased homocysteine excretion into urine throughout the 28 day period of ethanol administration; however, taurine did not prevent this increase. There was evidence of slight cholestasis in animals treated with alcohol and alcohol + taurine, as indicated by raised serum bile acids and alkaline phosphatase (ALP). The protective effects of taurine were attributed to the potential of bile acids, especially taurine conjugated bile acids (taurocholic acid) to inhibit the activity of some microsomal enzymes (CYP2E1). These in vivo findings demonstrate for the first time that hepatic steatosis and lipid peroxidation, occurring as a result of chronic alcohol consumption, can be ameliorated by administration of taurine to rats.     

Influence of gender on chronic ethanol-induced alterations in GABAA receptors in rats

Ethanol dependence, arising from chronic ethanol exposure, is associated with neuroadaptations of GABAA receptors, evidenced by alterations in various behaviors, receptor responsiveness and subunit gene expression. The present studies explored the effects of ethanol dependence in female rats for comparison with previous studies in our laboratory using male rats. We found that ethanol dependence resulted in differential effects on GABAA receptor gene expression in female rat cerebral cortex compared to ethanol dependent male rats. Notably, chronic ethanol consumption did not change GABAA receptor alpha 1 subunit peptide levels in ethanol dependent female rat cortex, in contrast to previously observed decreases in alpha 1 subunit expression in ethanol dependent male rat cortex. The effects of ethanol dependence on additional GABAA receptor subunit peptide levels (alpha 4, beta 2/3 and gamma 2) were similar, but not identical, between female and male rat cortex. When directly compared within the experiment, male and female rats had similar baseline bicuculline seizure thresholds and displayed a similar increase in seizure susceptibility during ethanol withdrawal. Ethanol withdrawn female rats were cross tolerant to the anticonvulsant effects of diazepam, similar to the findings in ethanol withdrawn male rats. Ethanol withdrawn female rats showed a dose-dependent enhancement of the anticonvulsant effect of the neuroactive steroid, THDOC (3 alpha,21-dihydroxy-5 alpha-pregnan-20-one) compared to control animals. This finding is similar to previous observations of increased sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-THP (3 alpha-hydroxy-5 alpha-pregnan-20-one) in ethanol withdrawn male and female rats. In addition, low dose administration of THDOC elevated seizure thresholds in ethanol withdrawn female but not male rats, suggesting that ethanol withdrawn female rats were more responsive to the anticonvulsant effects of this neurosteroid than were ethanol withdrawn male rats. These findings show that gender impacts on adaptations in GABAA receptors elicited by ethanol dependence. However, the physiological outcomes of the differential alterations are not clear. Taken together, these studies suggest that additional mechanisms, beyond effects on GABAA receptor gene expression are involved in the mediation of ethanol dependence and withdrawal.     

A mechanism for the formation of lower bainite

A diffusional mechanism for the formation of lower bainite is proposed based primarily on transmission electron microscopy (TEM) observations of isothermally reacted specimens of Fe-C-2 pct Mn alloys. The mechanism involves the initial precipitation of a nearly carbide-free ferrite“spine,” followed by sympathetic nucleation of“secondary (ferrite) plates” which lie at an angle to the initial“spine.” Carbide precipitation subsequently occurs in austenite at ferrite: austenite boundaries located in small gaps between the“secondary plates.” An“annealing” process then occurs in which the gaps are filled in by further growth of ferrite and additional carbide precipitation; the annealing out of ferrite: ferrite boundaries between impinged“secondary plates” completes this process. This annealing stage contributes to the final appearance of lower bainite sheaves as monolithic plates containing embedded carbides. The present mechanism accounts for the single variant of carbides oriented at an angle to the sheaf axis repeatedly reported in lower bainite; it is also consistent with the previous observation of one“rough” side and one“smooth” side of lower bainite“plates.” Formerly Graduate Student, Carnegie Mellon University. Formerly Visiting Professor, Carnegie Mellon University. This paper is based on a presentation made in the symposium“International Conference on Bainite” presented at the 1988 World Materials Congress in Chicago, IL, on September 26 and 27, 1988, under the auspices of the ASM INTERNATIONAL Phase Transformations Committee and the TMS Ferrous Metallurgy Committee.     

A study of the influence of gastric acid on the extension of regenerative epithelium of gastric ulcer

Nursing research is generally located within the paradigm of the social sciences, and therefore reflects the concerns and agenda of social research. In particular, nursing has become embroiled in the ongoing dispute between the advocates of qualitative and quantitative methodologies. However, it is argued in this paper that whereas the aim of social research is to develop knowledge, the aim of nursing research is primarily to advance practice. This paper offers an alternative model of nursing research which categorizes approaches to research not according to the methodology employed but on the extent to which the research process is likely to bring about change. These approaches are termed level 1, level 2 and level 3 research, where level 1 researchers are concerned with generating information for others to conceptualize and implement, while level 3 researchers see their aim as directly bringing about clinical change. Two approaches to level 3 research are suggested, and examples of projects at all three levels are examined. Finally, it is contended that only by adopting an appropriate model of research for a practice-based discipline can nursing address the real issues of relevance to nurses and patients in clinical settings.     

Reversal of ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade

Teenage drinking is a major problem in the United States, as well as abroad. Besides psychosocial implications, ethanol (EtOH) has detrimental effects on the reproductive system. Clinical problems associated with reduced reproductive hormones include osteoporosis, decreased muscle function, anemia, altered immune function, prostate involution, and decreased reproductive abilities. Education coupled with strategies aimed at preventing these deleterious consequences even in the face of continued EtOH intake is extremely important. We have tested the possibility that naltrexone, a drug currently used in patients to decrease alcohol craving, might also prevent the fall in the male hormone, testosterone, caused by EtOH exposure. Rats aged 35 days old (prepubertal), 45 days old (midpubertal), and 55 days old (late pubertal) were injected (intraperitoneally) with either saline, EtOH, naltrexone, or EtOH plus naltrexone. In the two older age groups, EtOH significantly suppressed testosterone, which was prevented by administration of naltrexone. In the youngest animals, there was no treatment effect presumably due to low basal levels of testosterone. EtOH similarly reduced luteinizing hormone (LH), but this suppression was not prevented by naltrexone. There was no consistent effect of any treatment on hypothalamic concentration of pro-LH releasing hormone (RH) (LHRH), LHRH, or on steady-state levels of LHRH mRNA. We conclude that, as animals progress through puberty, EtOH suppresses LH and testosterone. The testosterone decline can be prevented by opiate blockade with naltrexone, an effect primarily seen at gonadal level. Thus, naltrexone, a drug already used clinically to reduce EtOH intake, also has protective physiological effects on the endocrine system.     

Protection with lubeluzole against delayed ischemic brain damage in rats. A quantitative histopathologic study

BACKGROUND AND PURPOSE: Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N-methyl-D-aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus. METHODS: Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group). RESULTS: Posttreatment with lubeluzole (0.31 mg/kg i.v. bolus at 5 minutes and 0.31 mg/kg i.v. infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left (P = .002) and 113 in the right hemisphere (P = .013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons. CONCLUSIONS: Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.     

Antioxidants inhibit ethanol-induced gastric injury in the rat. Role of manganese, glycine, and carotene

BACKGROUND: Oxygen-derived radicals are implicated in the pathogenesis of tissue damage and ulcerogenesis. This study aimed to examine the effect of manganese, glycine, and carotene, oxygen radical scavengers, on ethanol-induced gastric lesions in the rat and on ethanol cytotoxicity in epithelial cell culture. METHODS: MnCl2 + glycine (12.5-50 mg/rat) were injected subcutaneously up to 6 h before oral administration of 1 ml of 96% ethanol, and 0.5 ml carrot juice or beta-carotene was given orally 30 min before the ethanol. Mucosal injury was evaluated 1 h later by gross and microscopic scoring. The effect of Mn2+ and carrot juice was also tested in monolayers of radiolabeled epithelial cells exposed to H2O2 + ethanol injury as expressed by the extent of the isotope leakage. RESULTS: Mn2+ and glycine pretreatment dose-dependently reduced ethanol-induced gastric lesion formation. Protection was maximal when treatment was applied 4 h before the insult. Gross damage was also markedly prevented by pretreatment with carotenes and dimethylthiourea (DMTU, 75 mg/kg intraperitoneally) but not by allopurinol. Mixtures of subtoxic concentrations of ethanol and H2O2 were highly lethal for epithelial cell monolayers. In this model, cell death was markedly attenuated by catalase, DMTU, Mn2+, and carrot juice. CONCLUSIONS: Ethanol-induced gastric mucosal damage may involve generation of oxygen-derived radicals, independent of the xanthine oxidase system. By acting as oxygen radical scavengers, Mn2+, glycine, and carotenes, like catalase and DMTU, provide significant gastroprotection.