The effect of amifostine on pathophysiological changes in vasogenic brain edema induced by an experimental cold injury model.

AIM: To investigate the effects of amifostine, a cytoprotective agent, on pathophysiological changes in vasogenic brain edema induced by an experimental cold injury model and to compare these changes with dexamethasone. MATERIAL AND METHODS: A total of 138 rats divided into 6 groups. Brain water content (BWC), malondialdehyde (MDA) concentration and myeloperoxidase (MPO) activity in brain tissue were calculated to evaluate the pathophysiological changes following experimental cold injury. In addition, effects of cold injury on cell structure were assessed with direct light and transmission electron microscopy (TEM). RESULTS: Extent of edema, MDA and MPO levels were significantly higher in cold injury groups than in controls. Although a decrease was noted in these parameters in both the amifostine and dexamethasone groups, the differences were significant only for MDA concentration in dexamethasone group, and for MPO activity in both groups. In addition, there was a significant difference between the group in which amifostine was administered prior to cold injury and dexamethasone group for MPO activity. Histopathologically, positive effects were observed in treatment groups. CONCLUSION: Despite several positive effects of amifostine, its superiority to dexamethasone could not be clearly demonstrated. Further experimental and clinical studies are warranted to better delineate the neuroprotective effects of amifostine.

Gastroprotective effect of orexin-A and heme oxygenase system.

BACKGROUND: Orexin-A, besides playing an important role in the mechanism of food intake, exhibits a potent gastroprotective action against the formation of acute gastric mucosal injury. The aim of the present study was to determine the effect of administered orexin-A against ischemia-reperfusion (I/R)-induced gastric injury on the expression of heme oxygenase (HO)-1 and HO-2 in gastric tissue. MATERIALS AND METHODS: Wistar rats were subjected to 30 min of ischemia followed by 3 h reperfusion. Orexin-A was infused at a dose of 500 pmol/kg/min during the I/R period. The lesion area was measured by stereomicroscope. The myeloperoxidase activity and 4-hydroxinonenol-malondialdehyde content of gastric mucosa were evaluated spectrophotometrically, and the gastric tumor necrosis factor-α was measured by enzyme linked immune sorbent assay. The expression of HO-1 and HO-2 was determined by Western blotting analysis. RESULTS: Orexin-A significantly decreased the I/R-induced gastric lesions, myeloperoxidase activity, and 4-hydroxinonenol-malondialdehyde concentration in gastric tissue exposed to I/R. The gastroprotective effect of orexin-A in gastric I/R model was accompanied by the increase in HO-2 expression and the decrease in HO-1 expression. CONCLUSIONS: Orexin-A exerts a protective action on gastric mucosa subjected to I/R, and this effect is associated with the reduction of neutrophil infiltration and lipid peroxidation in gastric tissue in addition to the increase in HO-2 expression due to the administration of orexin-A.

Effect of orexin-A on phagocytic activity of peritoneal macrophage in starved rats.

The aim of this study was to investigate the effect of fasting-induced orexin-A (OXA) on inflammation and macrophage phagocytic activity. Fifty six male wistar rats were fasted for 36 h to stimulate OXA synthesis. In 24 rats, air pouches were induced subcutaneously in the intrascapular area. After (6 h) carrageenan injection into the pouches, the contents of the air pouches were removed. The exudate volume, protein content and cell count were measured. After the determination of fasting on inflammation, the peritoneal macrophages were collected from 32 rats to investigate the effect of fasting-induced OXA on macrophage phagocytic activity. Plasma OXA levels were markedly higher in fasted rats compared with control rats. The phagocytic capability of peritoneal macrophages was obtained as a percentage of phagocytosing macrophages and number of phagocytosed particles per cell. In spite of increased blood OXA level SB-334867, selective orexin type 1 receptor antagonist (10 mg/kg) did not change phagocytic activity of peritoneal macrophages. These findings indicate that 36 h fasting-induced OXA has no significant effect to phagocytosis of peritoneal macrophages.

Endogenous orexin-A modulates gastric motility by peripheral mechanisms in rats.

Orexin-A (OXA) and orexin receptor type 1 (OX1R) are found in enteric nervous system and smooth muscle cells in the digestive tract. Fasting is a stimulant for OXA synthesis. The aim of the present study was to investigate central and peripheral effects of endogenous OXA on gastric motility. Endogenous OXA synthesis was induced by 36h fasting. Vagotomy was used to evaluate N.vagus-mediated effects of OXA. Gastric emptying and interdigestive gastric motility were measured by spectrophotometric and manometric methods, respectively. Rats were pretreated with OX1R antagonist SB-334867 prior to measurements. Plasma OXA concentration was assayed with radioimmunoassay while preproorexin (PPO) expression was determined with Western blotting in gastric and hypothalamic tissues. OXA immunoreactivity in antrum was determined with immunohistochemistry. Plasma OXA level, PPO protein expression and OXA immunoreactivity were significantly increased in response to 36h fasting. Endogenous OXA facilitated gastric emptying and inhibited gastric interdigestive motility. As these effects were abolished with SB-334867, it is likely that gastrokinetic effects of OXA are mediated via OX1R. Vagotomy did not alter OXA-mediated effects. According to current data, OXA is up-regulated both centrally and peripherally upon fasting. Endogenous OXA accelerates gastric emptying while it inhibits interdigestive motility.

Expressions of inducible nitric oxide synthase and cyclooxygenase-2 in gastric ischemia-reperfusion: role of angiotensin II.

BACKGROUND: Angiotensin II contributes to the pathogenesis of inflammation induced by ischemia-reperfusion (I/R) in various organs. Angiotensin II increases vascular permeability that initiates the inflammatory process and leads to the migration of inflammatory cells into the tissue. The aim of the present study was to investigate the effect of angiotensin II on ischemia-reperfusion induced expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in rat stomachs exposed to ischemia-reperfusion. METHODS: Wistar rats were randomly separated into five groups: sham operated, I/R, I/R plus candesartan (an AT1 receptor antagonist), I/R plus PD123319 (an AT2 receptor antagonist), and I/R plus captopril (an angiotensin-converting enzyme inhibitor). Candesartan (1mg/kg/d), PD123319 (3mg/kg/d), and captopril (20mg/kg/d) were given subcutaneously twice a day for 5 d before I/R. The rats were submitted to gastric ischemia by clamping the celiac artery for 30min followed by 24h reperfusion. RESULTS: Candesartan decreased the neutrophil accumulation, iNOS expression, and increased NOx level, COX-2 expression in the gastric tissue exposed to I/R compared with I/R group. PD123319 did not change the neutrophil accumulation, iNOS expression, PGE(2), or NOx levels, but increased the expression of COX-2 in the gastric tissue exposed to I/R. However, captopril did not play any role in I/R induced change in gastric mucosa. CONCLUSIONS: The results suggest that Angiotensin II via angiotensin II type 1 receptor increases the accumulation of neutrophils and iNOS expression and plays a significant role in mediating inflammation in gastric mucosa exposed to I/R.

Effect of orexin-a on ischemia-reperfusion-induced gastric damage in rats.

BACKGROUND: Orexins are involved in the regulation of sleeping behavior and energy homeostasis, and they are also implicated in the regulation of gastrointestinal functions. Previous reports have demonstrated the expression of orexin receptors in the gastrointestinal system. The aim of this study was to investigate the gastroprotective effect of orexin-A in ischemia-reperfusion-induced gastric mucosal injury. METHODS: The gastric ischemia-reperfusion model was established by clamping the celiac artery for 30 min and reperfusing for 60 min. Orexin-A was administered in doses of 500 pmol.kg(-1).min(-1) by infusion throughout the ischemia-reperfusion period. The mean lesion area, gastric prostaglandin E2 and mucus content, myeloperoxidase activity, and production of thiobarbituric acid reactive substances were measured. RESULTS: Orexin-A significantly attenuated the ischemia-reperfusion-induced gastric lesions and also decreased myeloperoxidase activity and the thiobarbituric acid reactive substances content in gastric mucosa of rats exposed to ischemia-reperfusion. However, the decline in gastric prostaglandin E2 and mucus content was not restored by orexin-A treatment. CONCLUSIONS: Orexin-A exhibited a gastroprotective effect against ischemia-reperfusion-induced lesions by decreasing neutrophil activation and lipid peroxidation.

Effect of docosahexaenoic acid on macrophage functions of rats.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid which has been demonstrated to exhibit anti-inflammatory effects. The objective of this study was to determine the effect of DHA on phagocytic and chemotactic activities of peritoneal macrophages obtained from rats. DHA was dissolved in 1 ml of corn oil at dose of 36 mg/kg/day and given via oral gavage for 4 weeks. Control rats received 1 ml/day corn oil as vehicle. At the end of the treatment period, peritoneal macrophages were isolated and chemotactic and phagocytic activities were assayed. Chemotactic and phagocytic activities were reduced in rats fed with DHA. These results demonstrated the effect of DHA in modulating immune activities of rat peritoneal macrophages.

Effect of chronic stress and L-carnitine on rat stomach.

BACKGROUND AND AIM: L-Carnitine is an essential cofactor in the mitochondrial transfer of fatty acids, and it is also a scavenger of free radicals in mammalian tissues. The aim of the study was to determine the effect of L-carnitine on chronic restraint stress-induced gastric mucosal injury. METHODS: Wistar rats were applied restraint stress (1 h/day) and L-carnitine (50 mg/kg) for 21 days. The lesion index, prostaglandin E(2) and mucus content, lipid peroxidation, superoxide dismutase, and catalase activity in gastric mucosa were evaluated. RESULTS: Chronic restraint stress increased the lesion index, lipid peroxidation, and superoxide dismutase activity in gastric mucosa, and it decreased prostaglandin E(2) and mucus content. L-Carnitine treatment prevented the stress-induced increase in lesion index, lipid peroxidation and a stress-induced decline in prostaglandin E(2), and mucus content in gastric mucosa, but it increased catalase activity. CONCLUSIONS: L-Carnitine prevents the occurrence of lesion by strengthening the gastric mucosal barrier and by reducing lipid peroxidation against the harmful effects of chronic restraint stress.

Prostaglandins, capsaicin-sensitive sensory nerves and neutrophil infiltration, but not nitric oxide, contribute to cold restraint stress-induced gastric adaptation in rats.

The aim of the present study was to determine the role of prostaglandins (PG), nitric oxide (NO) and capsaicin-sensitive sensory nerves in neutrophil infiltration in gastric adaptation to cold restraint stress in rats. Wistar rats were exposed to single or repeated cold restraint stress for 3.5 h every other day for up to 4 days. Prior to repeated stress, rats were pretreated with NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, s.c.), indomethacin (10 mg/kg, s.c.) or capsaicin (125 mg/kg, s.c.). The extent of gastric mucosal lesions was evaluated histologically and myeloproxidase (MPO) activity, PGE2, NO and calcitonin gene-related peptide (CGRP) levels were measured in gastric tissue. Cold restraint stress produced haemorrhagic lesions and reduced PGE2 and CGRP levels in the stomach, with an increase in MPO activity and NO levels. Repeated stress insults reduced stress-induced gastric damage, NO production and MPO activity, with an increase in PGE2 and CGRP levels compared with rats exposed to single cold restraint stress. Adaptation to cold restraint stress was prevented by indomethacin and capsaicin pretreatment, but not by L-NAME. We conclude that the stomach has the ability to adapt to repeated exposure to cold restraint stress and that the adaptation, via inhibition of neutrophil infiltration, is mediated, at least in part, by endogenous PG and CGRP.

Effect of sulfite on macrophage functions of normal and sulfite oxidase-deficient rats.

Sulfite has both an endogenous and an exogenous provenance in the mammalian tissues. The aim of the present study was to assess the effect of sulfite on macrophages functions in normal or sulfite oxidase deficient rats. Rats were divided into eight groups; (1) control group, (2) sulfite group (the rats received sodium meta bi-sulfite (25 mg/kg) in drinking water for 6 weeks), (3) vitamin E group (the rats received Vit E (50 mg/kg) by gavage for 6 weeks), (4) sulfite group+Vit E, (5)sulfite oxidase deficient group (the rats received high-W/Mo-deficient diet. The activity of sulfite oxidase was reduced in rats maintained on the high-W/Mo-deficient diet during the first 21 days of treatment. After the sulfite-oxidase deficiency, the rats continued to receive high-W/Mo-deficient diet for 6 weeks.), (6) sulfite+sulfite oxidase deficient group, (7) Vit E+sulfite oxidase deficient group, and (8) sulfite+Vit E+sulfite oxidase deficient group. Sulfite caused a significant increase in phagocytic and chemotactic activities of peritoneal macrophages. In sulfite-oxidase deficient rats, the increase in phagocytic and chemotactic activities in peritoneal macrophages after sulfite intake was found more than the control rats. Vit E supplementation prevented sulfite induced increase in macrophages functions. These results show that the macrophage functions are sensitive to sulfite intake. The effect of sulfite on macrophage functions may be related to reactive oxygen species. Because Vit E administration was able to modulate significantly sulfite-induced changes in the functions of peritoneal macrophages.

Effect of stress-induced lipid peroxidation on functions of rat peritoneal macrophages.

The aim of the present study was to investigate the effects of stress-induced lipid peroxidation on macrophages' functions. Animals were subjected to 4 h immobilization at 4 degrees C in restraining devices. The peritoneal macrophages obtained from rats exposed to cold and restraint stress exhibited an increase in lipid peroxidation and a decline of chemotaxis and phagocytosis compared with control rats. After supplementation with vitamin E, the increment in thiobarbituric acid reactive substances (TBARS) content as the oxidative stress marker and the decline of chemotaxis and phagocytosis in peritoneal macrophages observed during cold-restraint stress was significantly removed. No significant change in catalase activity of peritoneal macrophages was observed in groups exposed to cold-restraint stress and treated with vitamin E. These findings indicate that phagocytic and chemotactic capacities of peritoneal macrophages are decreased by cold-restraint stress and this effect of stress may be related to lipid peroxidation.