Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats

A silent process involving both neural and vascular structures in diabetic retina persists for several years before clinically detectable retinopathy. Recordings of the electroretinogram (ERG) and visual evoked potential (VEP) provide early warning of abnormalities in the visual pathway of diabetic patients and animal models. Treatment of streptozotocin-diabetic rats for 1 or 2 months with the heat-shock protein coinducer bimoclomol, a drug ameliorating experimental neuropathy, prevented and corrected the abnormal increase in latency and reduction of amplitude of ERG and VEP waves both in acute and chronic experiments. Improvements may be explained by cytoprotective effect of bimoclomol on retinal glia and/or neurons against diabetes-related ischemic cell damages. These findings suggest that bimoclomol may have future therapeutic use in diabetic retinopathy.     

Germinated barley foodstuff improves constipation induced by loperamide in rats

The effects of germinated barley foodstuff (GBF) derived from the aleurone and scutellum fractions of germinated barley low-lignified hemicellulose were examined in Sprague-Dawley rats with constipation induced by loperamide by addition to the diet (2 mg/kg body weight). Bowel movements were higher in the GBF-fed rats than in the cellulose-fed rats used as a control. Fecal water content was also higher in the GBF-fed rats. The concentration of short chain fatty acids in cecal content, especially butyrate, was significantly higher in the GBF-fed rats than in the cellulose-fed rats. These findings suggested that GBF helps normalize defecation not only in diarrhea but also constipation.     

Enrichment to odors improves olfactory discrimination in adult rats.

The authors tested how prior odor enrichment affects the spontaneous discrimination of both preexposed and novel odors. Experimental rats were exposed to single odors or to pairs of similar or dissimilar odors for 1-hr periods twice daily over 20 days. Spontaneous discriminations between pairs of similar odors were tested before and after the odor exposure period using an olfactory habituation task. The authors found that (a) experimental rats did not spontaneously discriminate similar odor pairs before the exposure period, whereas they spontaneously discriminated them after the enrichment period, and (b) the improvement of performance was not selective for the odors used during enrichment. These results show that odor experience changes perception in the manner predicted based on other groups' electrophysiological experiments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes

Whole muscle contractile characteristics and fatigue resistance were studied in male patients with chronic heart failure (n = 6) and in healthy control subjects (n = 6). Maximum voluntary isometric strength in the major muscle groups of leg (plantar flexors and knee extensors) and arm (elbow extensors and elbow flexors), was found to be similar for both groups of subjects. However, a faster isometric twitch time course was observed in the plantar flexor and knee extensor muscles of heart failure chronic patients. The poor resistance to fatigue in the knee extensors of chronic heart failure patients was confirmed in the present study, but using twitch interpolation this was shown not to be due to poor activation. The plantar flexors of chronic heart failure patients also showed a tendency to be less resistant to fatigue, even when the muscle was activated by direct electrical stimulation. The present study shows that independent of muscle strength, patients with chronic heart failure may possess muscles that are faster to contract and less resistant to fatigue. However, it seems this increased fatigability is not due to poor muscle activation.     

Oral absorption of D-oligopeptides in rats via the paracellular route

Mortality differs substantially between the Flemish and Walloon regions is Belgium. The question remains as to whether the health status of both populations varies in a similar way. The difference in healthy life expectancy, an indicator of population health, between the Flemish and Walloon regions was therefore assessed. In 1989-1990 a cross-sectional survey in the general population was performed in which 2640 persons were selected by a multistage random process. Perceived health status was determined through a validated question: "On the whole, how would you describe your health for the moment? Would you say it is very good/good/fair/rather bad/bad?" The prevalence of "being in good health (very good to fair)" was combined with mortality data (Sullivan method) to estimate the healthy life expectancy (HLE), and the following results were found. Among males, life expectancy (LE) and HLE at age 15 was 58.9 years and 56.5 years in the Flemish region, compared with 56.6 and 50.2 years in the Walloon region. At age 65, LE and HLE in the Flemish region was 14.3 and 13.3 years, and only 13.2 and 9.2 years in the Walloon region. Women at age 15 had an LE and HLE in the Flemish region of 65.2 years and 61.3 years, compared to 63.9 and 58.1 years in the Walloon region. At age 65, both the LE and the HLE in the Flemish region were higher, with LE at 18.5 versus 17.7 years, and HLE at 16.0 versus 14.3 years. Similar results were obtained when the criteria of "being in good health" were restricted to those indicating their health to be very good or good. In conclusion, the data indicate that the population in the Walloon region not only has a shorter life but apparently also has a shorter healthy life. Research is needed to explain what proportion of these differences can be attributed to differences in the prevalence of diseases, cultural differences and socio-economic differences.     

Growth hormone improves cardiac function in rats with experimental myocardial infarction

Glioblastoma multiforme is a highly invasive primary brain tumor, which is known to strongly express the CD44 cell adhesion receptor. A number of experimental studies suggest that the interaction of this receptor with extracellular matrix (ECM) proteins such as hyaluronic acid may in part mediate human glioma cell adhesion and invasion of brain tissue. Although the expression of CD44 and its spliced variants in brain tumors have been extensively studied, there have been no reports localizing its expression to the invasive margin of the tumor. The authors used immunoelectron microscopy to investigate the expression patterns of CD44 in an in vitro organotypic invasion assay. Tumor spheroids initiated from the U373 MG human glioblastoma line were confronted with fetal rat brain aggregates in a spheroid coculture system. The CD44 expression appeared at the interface between glioblastoma tumor spheroids and brain tissue, as well as in the spheroid itself. CD44 immunoreactivity was not detectable in mature 21-day fetal brain aggregates. The findings provide direct evidence that CD44 is expressed at the confrontational invasive border between glioblastomas and brain tissue, further supporting its role in glioma cell-ECM recognition and attachment.     

Pyrrolidine dithiocarbamate improves the septic shock syndromes in spontaneously hypertensive rats

1. The aim of the present study was to evaluate the effect of pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor-kappa B (NF-kappa B), on septic shock induced by Escherichia coli lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHR). 2. After injection of LPS in SHR, a marked decrease in blood pressure was observed at 3 h and vascular hyporeactivity to noradrenaline (NA) was observed after 1 h. A marked increase in plasma levels of tumour necrosis factor-alpha (TNF-alpha) and nitrite (an indicator of nitric oxide) was also observed in SHR. 3. The delayed hypotension and hyporeactivity to NA induced by LPS were significantly reserved by pretreatment of rats with PDTC (10 mg/kg). The increase in plasma levels of TNF-alpha and nitrite in LPS-treated groups was also significantly suppressed by PDTC pretreatment. In addition, the survival time of SHR treated with LPS was significantly prolonged by PDTC pretreatment. 4. The present ex vivo study demonstrates that the NA-induced contraction is attenuated and the L-arginine-induced relaxation is enhanced in aortic rings obtained from LPS-treated SHR. Both the reduction of the NA-induced contraction and the increase of L-arginine-induced relaxation were reversed by pretreatment with PDTC. However, the relaxation elicited by acetylcholine (ACh) was not affected in LPS-treated SHR when compared with sham-operated SHR. In addition, the ACh-induced relaxation in LPS-treated SHR was not affected by PDTC pretreatment. 5. In normotensive Wistar-Kyoto (WKY) rats, LPS had mild effects on blood pressure, vascular hyporeactivity and plasma levels of TNF-alpha and nitrite. At a higher dose, PDTC (10 mg/kg) also prolonged survival time and improved haemodynamics in LPS-treated WKY rats. In the ex vivo study, it was noted that the relaxation elicited by ACh was significantly (P < 0.05) attenuated in LPS-treated WKY rats. This attenuation of the ACh-induced relaxation by LPS in WKY rats was significantly reversed by pretreatment with 10 mg/kg PDTC. 6. In conclusion, PDTC prolongs survival time in rats with endotoxaemia and improves the septic shock syndromes both in vivo and ex vivo. Thus, we propose that PDTC may be of use in septic patients.     

Fractional absorption of L-carnitine after oral administration in rats: evaluation of absorption site and dose dependency

We evaluated the fractional absorption of L-carnitine, a gamma-amino acid essential cofactor for the transfer of long-chain fatty acids, in rats in vivo after oral administration to determine its absorption behavior. At both low (0.05 micromol/rat) and high (100 micromol/rat) doses, L-carnitine was recovered only from the region of the cecum and below at 10 h after administration. During a major shift in distribution from cecum at 10 h to feces at 24 h, there was no significant change in the total recovery at each dose, suggesting that L-carnitine absorption is negligible in the cecum and the large intestine (colon and rectum). However, the recovery of L-carnitine was incomplete and the fraction recovered was larger at the high dose than at the low dose. The fractions absorbed were estimated to be 96.7 and 33.0% for the low and high doses, respectively, as these were the fractions that disappeared from the gastrointestinal tract. These values were comparable with 100 and 42%, respectively, of bioavailability values by the pharmacokinetic analysis of plasma concentration data in our preceding study [Matsuda et al., Biopharmaceutics & Drug Disposition, in press]. These results suggest that L-carnitine is significantly absorbed only in the small intestine, without undergoing first-pass degradation, and in a dose-dependent manner presumably due to the involvement of saturable transport by L-carnitine carriers. Consistent with the suggestions in vivo, L-carnitine absorption in the closed intestinal loop in situ was concentration-dependent in the small intestine but not in the large intestine, and the apparent membrane permeability in the large intestine was smaller by an order of magnitude than that of passive transport in the small intestine. These findings support our preceding kinetic modeling strategy assuming the small intestine to be the sole absorption site, and should be of help in guiding studies on development of more efficient oral L-carnitine delivery strategies.     

Effect of dietary fats on the incidence of 7,12-dimethylbenz(a)-anthracene-induced tumors in rats

Female rats have been fed high fat diets containing either polyunsaturated or saturated fat. After being fed either of the diets for 4 weeks, some of the animals received an intragastric dose of 7,12-dimethylbenz(a)anthracene (DMBA). At this point, the diets of half of the animals were interchanged so that animals previously fed the polyunsaturated fat diet were fed the saturated fat diet and vice versa. The cumulative incidence of tumor-bearing rats among DMBA-dosed rats was greater when the polyunsaturated fat diet was fed. The mean induction time of tumors decreased and the proportion of tumor-bearing rats which developed malignant tumors increased when the polyunsaturated fat diet was fed. This promotional effect of the polyunsaturated fat diet was exerted only when the diet was fed after DMBA administration.     

Prevention of coprophagy modifies magnesium absorption in rats fed with fructo-oligosaccharides

We developed a new type of anal cup for prevention of coprophagy and determined whether the absorption of Ca and Mg and the stimulatory effects of feeding fructo-oligosaccharides (FO) on the absorption of Ca and Mg were altered by prevention of coprophagy in rats. Rats were fed on a FO-free diet or a diet containing 50 g FO/kg for 2 weeks with or without prevention of coprophagy. FO-feeding increased the apparent absorptive ratio of Ca and Mg in rats with or without prevention of coprophagy. However, in the FO-fed groups the absorptive ratio of Mg in rats with prevention of coprophagy was higher than in rats without prevention of coprophagy. The Ca content of the femur was higher in rats fed on the FO-diet than in rats fed on the FO-free diet both with and without coprophagy. In conclusion, FO-feeding increased the absorption of Ca and Mg in rats both with and without coprophagy. Moreover, prevention of coprophagy enhanced the absorption of Mg in rats fed with FO. Coprophagy has to be considered when the effects of luminal fermentation or mineral absorption are examined in rats.     

Effect of oral adsorbent AST-120 on cyclosporin absorption in rats

The oral adsorbent AST-120 is used to inhibit the progression of renal failure by adsorbing uraemic toxins in the gastrointestinal tract. When AST-120 is administered to patients receiving immunosuppressive medicines, it is important to study the effect of AST-120 on the amount of these and other drugs absorbed. We have, therefore, studied the in-vitro adsorption of cyclosporin by AST-120 and investigated the effect of oral administration of AST-120 on the absorption of cyclosporin in rats. The in-vitro adsorption ratios of AST-120 for cyclosporin were more than 80%. When pure cyclosporin powder was administered with AST-120, blood cyclosporin concentrations were significantly higher than when cyclosporin was administered alone. When cyclosporin dissolved in medium-chain triglyceride was administered to rats by intramuscular injection there was no significant difference in the blood cyclosporin concentration of rats given combined AST-120 and cyclosporin and those given cyclosporin alone. There was no significant difference between the serum concentration of total bile acids, in rats receiving combined oral AST-120 and cyclosporin dissolved in olive oil, and those receiving orally solely a solution of cyclosporin dissolved in olive oil. These results suggest that oral administration of AST-120 accelerates the absorption of orally administered cyclosporin from the gastrointestinal tract and does not affect the metabolism of cyclosporin. When a solution of cyclosporin in olive oil is administered orally, however, oral administration of AST-120 has no influence on cyclosporin absorption and does not affect the enterohepatic circulation of bile acids.     

Percutaneous absorption and disposition studies of methotrexate in rabbits and rats

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples.     

Gastric digestion modifies absorption of butterfat into lymph chylomicrons in rats

Our objective was to characterize the time course of mesenteric lymph output, lipid composition and size of lymph chylomicrons in rats given gastric infusion of lipid emulsions containing defined fractions of butterfat, palm oil or corn oil. The concentrations of cholesterol, triacylglycerol (TAG) and phospholipid in lymph obtained before lipid infusion were 1.4-2.5-fold greater in rats chronically fed palm oil or solid butterfat compared with corn oil or liquid butterfat (P = 0.02). Total lymph chylomicron TAG output (mg/24 h) stimulated by gastric lipid infusion was 21% greater with corn oil compared with all saturated fats (P = 0.02). Total lymph chylomicron cholesterol output was 1.3-8.6-fold greater than the amount infused in all groups (P = 0.03) and was independent of the amount of cholesterol infused. The size distribution as well as the mean, median and modal diameters of lymph chylomicrons isolated during peak lymphatic TAG output were not significantly different among treatments. The fatty acid and TAG profiles of lymph chylomicrons obtained from rats infused with corn or palm oil did not differ significantly from that of the emulsion infused. In contrast, gastric lipolysis of butterfat significantly modified the lipid composition of lymph chylomicrons. We observed progressive disappearance of short- and medium-chain fatty acids in gastric contents and an absence of detectable short-chain fatty acids with concurrent proportionate increases in long-chain fatty acids and large TAG molecules in lymph chylomicrons compared with butterfat emulsions. These studies demonstrate that gastric digestion is an important modifier of lipid absorption.     

In vivo absorption of carbohydrates in rats with gastro-intestinal radiation syndrome

Absorption of glucose and sucrose by intestine from supralethally irradiated rats was investigated using an in vivo preparation. An activation of glucose absorption one day day after exposure is followed by a marked fall in glucose and sucrose absorption on day 3. Experiments under different conditions of loading indicate that at 20 hours active transport of glucose is already impaired although the maximum velocity is increased. After 3 days maximum velocity and active transport decrease markedly. Inverstase activity increases after 20 hours, but this is not accompanied by an increased sucrose absorption. The defect in sucrose absorption 72 hours after irradiation is paralleled by a decrease in invertase activity.     

Effect of dietary fats and sesamin on the lipid metabolism and immune function of Sprague-Dawley rats

We examined the effect of three dietary fats, safflower oil (SAF) rich in linoleic acid, borage oil (BOR) rich in gamma-linolenic acid, and perilla oil (PER) rich in alpha-linolenic acid, on the lipid metabolism, and chemical mediator and immunoglobulin levels in Sprague-Dawley rats, as well as the dietary effect of sesame-derived antioxidative sesamin. The serum cholesterol, phospholipid, triglyceride, prostaglandin E2 level and splenic leukotriene B4 level were lower in the rats fed on BOR or PER than in those fed on SAF. SES feeding suppressed the expression of the lipid-decreasing effect of BOR, but not in the rats fed on PER. In respect of the fatty acid composition of the liver and spleen, PER feeding gave a lower arachidonic acid level, and higher eicosapentaenoic and docosahexaenoic acid levels than SAF feeding did, while the effect of BOR feeding was marginal. The effect of SES feeding on fatty acid composition was much smaller than that of dietary fats. In respect of immunoglobulin production, PER + SES feeding gave the lowest IgE productivity in the mesenteric lymph node lymphocytes. These results suggest that PER feeding regulated lipid metabolism and exerted an anti-allergic effect by a different mechanism from that with BOR feeding.     

Diet selection improves morphine's antinociceptive actions in rats with streptozotocin-induced diabetes.

Following the administration of the diabetogenic drug streptozotocin, rats selecting their diet from separate sources of macronutrients (e.g., proteins, fats, and carbohydrates) demonstrated less severe symptoms of diabetes than did rats fed ground Purina chow or a composite diet containing the same nutrient sources as found in the self-selection diet but in the proportions found in chow. After the induction of diabetes, rats selecting their own diet ate and drank less, weighed more, and had more adipose tissue and lower blood glucose levels than did rats consuming chow or the composite diet. In addition, rats choosing their diet were more sensitive to morphine's pain-relieving properties than were rats in the other 2 dietary groups. Rats given the self-selecting diet consumed more protein and fat and less carbohydrate than did those eating a single diet. Data suggest that rats must select their diet preceding and following the induction of diabetes for amelioration of diabetic symptoms to occur. These results indicate that diet can contribute to the severity of diabetes and could be used as an adjunct to standard treatment of the disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glutamine-supplemented parenteral nutrition improves gut mucosa integrity and function in endotoxemic rats

Seventy-seven pancreatic adenocarcinomas (60 Spanish and 17 Italian) were tested for Ki-ras gene mutations by analysis of polymerase chain reaction amplified sequences. Mutations involving codon 12 (GGT; gly) were detected in 16 Italian and 46 Spanish cases (80.5% in total). All Italian mutations involved the second base and were G to A transitions (GAT; asp) in 8 cases and G to T transversions (GTT; val) in the remaining 8. Forty-two Spanish mutations were characterized. Thirty-eight were at the second and 4 at the first base: asp in 24 cancers, val in 14, arg (CGT) in 2 and cys (TGT) in 2. Previous European studies and our present data show that 149 of the 186 pancreatic cancers harbored a codon 12 Ki-ras mutation (80%), the large majority affecting the second base (73%), with a transitions/transversions ratio of 1.3:1. However, the mutational pattern of cancers of the different European countries shows remarkable differences, both in the site of the mutation (first or second base) and in the ratio of transitions over transversions. Moreover, a significant subgroup of pancreatic carcinomas do not harbor Ki-ras mutations. The classification of pancreatic cancers, according to the presence or absence, and type of Ki-ras mutation, may be of importance in epidemiological studies. A critical reappraisal of existing epidemiological data, through a retrospective genotypic study using paraffin-embedded cancer samples, may reveal significant correlations with specific genotoxic agents.