Sprague-Dawley Strain Research Articles

Dysfunctional play and dopamine physiology in the Fischer 344 rat

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher pre-pulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors.

Effects of long-term vitamin K 1 (phylloquinone) or vitamin K 2 (menaquinone-4) supplementation on body composition and serum parameters in rats

Vitamin K is a cofactor for γ-glutamyl carboxylase, which is an essential enzyme for the γ-carboxylation of vitamin K-dependent proteins such as osteocalcin and matrix Gla protein. Although it has been suggested that vitamin K plays an important role in the improvement of bone metabolism, the relationship between dietary vitamin K intake and bone metabolism has not been thoroughly investigated. Moreover, vitamin K is thought to have other actions beyond influencing the γ-carboxylation status. In the present study, we examined the effects of the long-term addition of phylloquinone (PK) or menaquinone-4 (MK-4) to a control diet on bone mineral density, bone strength, body composition, and serum parameters in rats. A total of 23 female Sprague–Dawley strain rats (6 weeks old) were divided into three groups: basic control diet group, PK diet (PK: 600 mg/kg diet) group, and MK diet (MK-4: 600 mg/kg diet) group. Three months after starting the experimental diet, the addition of PK to the basic control diet significantly increased the bone mineral density (BMD) of the femur ( p < 0.05). In the MK group, there was no significant difference in the BMD of the femur. However, two types of bone strength parameter: the minimum cross-sectional moment of inertia and the polar moment of inertia, were significantly higher in the MK group than in the control ( p < 0.05, respectively). Furthermore, the femoral bone parameters (the width, dry weight and ash weight, and cortical, cancellous, trabecular, and total bone mineral contents) in the MK group were increased significantly compared with the control. Interestingly, the addition of PK or MK-4 significantly decreased the total fat accumulation ( p < 0.01 and p < 0.05, respectively), and serum triglycerides were reduced by 48% in the PK group and 29% in the MK group compared with the control. There were no significant differences in the levels of serum calcium, phosphorus, alkaline phosphatase, growth hormone, insulin-like growth hormone-1, insulin-like growth hormone binding protein-3, and cross-linked N-teleopeptide of type I collagen among the three groups. This is the first study to demonstrate the effect of the long-term addition of PK or MK-4 to the control diet on body composition and serum parameters in an in vivo system using rats. Further studies on the mechanism of vitamin K supplementation in the regulation of bone metabolism would provide valuable data on the prevention of lifestyle-related disorders, including osteoporosis.

Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats

A major hypothesis of depression postulates that a dysregulation of the neurotrophin systems is directly involved in the pathophysiology of depression, and that restoration of such deficits may underlie the therapeutic efficacy of antidepressant treatment. One key finding supporting this hypothesis is upregulation of brain derived neurotrophic factor (BDNF) in the hippocampus after antidepressant treatment. Here, we further test the hypothesis of BDNF involvement in antidepressant action in a genetic rat model of depression after chronic oral treatment with escitalopram, nortriptyline or placebo. Active treatments had significant behavioural antidepressant-like actions in female rats of the Flinders Sensitive Line (FSL) and non-selected Sprague Dawley (SD) rats, while Flinders Resistant Line (FRL) rats were unaffected. Escitalopram, but not nortriptyline, markedly reduced BDNF mRNA levels in the dentate gyrus of FSL rats. The BDNF downregulation was common to the four major promoters of the gene. Treatments did not affect BDNF expression in FRL or SD strains. We conclude that the antidepressant effects of escitalopram and nortriptyline, two common drugs with different pharmacological profiles, appear to be unrelated to the regulation of hippocampal BDNF expression in female rats. These results indicate that the tropic hypothesis of depression has limitations and emphasize the need for validated disease models of depression to assess potential treatment targets.

Dyspepsia in Nonsteroidal Anti-inflammatory Drugs Gastropathy

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) gastropathy is a common complication, which has characteristic symptoms of dyspepsia syndrome. Mostly, it includes epigastric discomfort with bloating and nausea. The aim of this study was to provide evidences that clinical symptoms of dyspepsia are related to macroscopic changes of gastric form in rats, which are expected to be applied in human. Method: The study was conducted in 20 white rats (Rattus norvegicus, Sprague-Dawley strain) at the Department of Pathology and Clinical Reproduction, Bogor Agricultural University between January and December 2008. The rats were divided to treatment group and control group and each group consisted of 10 rats. Acetyl salicylic acid (ASA/aspirin) was administered at 400 mg dose, diluted in distilled water and was given to the treatment group using gastric cannula, once daily for three days period; while the control group had received aquabidest only. Subsequently, necropsies were conducted for both groups, followed by macroscopic observation and measurement of sagittal and transversal diameter. Gastric incisions along the minor curvature were performed in both groups to recognize any macroscopic changes of gastric mucosa. ANOVA test was utilized for data analysis, which was followed by Duncan test when the results were significant. Results: Gastric diameters in treatment group with positive lesion were significantly different from the control group and the treatment group with negative lesion on anthrum/pylorus region, with p < 0.05. Conclusion: Prominent gastric dilatation at anthrum/pylorus region found in the treatment group may become the initial cause and signs of dyspepsia in human. Keywords: NSAID gastropathy, dyspepsia, NSAIDs/aspirin, gastric dilatation

Antioxidant and antihepatotoxic effect of Spirulina laxissima against carbon tetrachloride induced hepatotoxicity in rats

The vast biodiversity of nature provides bioactive compounds that may be useful in the fight against chronic diseases. This study was designed to investigate the protective effects of the ethanol extract of Spirulina laxissima West (Pseudanabaenaceae) (EESL) against carbon tetrachloride (CCl(4)) induced hepatotoxicities in rats. Male albino rats of Sprague-Dawley strain were treated orally with the ethanol extract of S. laxissima (50, 100 mg kg(-1) body wt.) 1 h before each CCl(4) administration. The ethanol extract of S. laxissima showed the maximum antioxidant property in vitro. There were statistically significant losses in the activities of antioxidant enzymes and an increase in TBARS and liver function marker enzymes in the serum of the CCl(4)-treated group compared with the control group. However, all the tested groups were able to counteract these effects. The antioxidant activity of the extracts might be attributable to its proton-donating ability, as evidenced by DPPH. In the present study, the decline in the level of antioxidant observed in CCl(4)-treated rats is a clear manifestation of excessive formation of radicals and activation of the lipid peroxidation system resulting in tissue damage. The significant increases in the concentration of antioxidant enzymes in tissues of animals treated with CCl(4) + EESL indicate the antioxidant effect of EESL. This study suggests that EESL can protect the liver against CCl(4)-induced oxidative damage in rats, and the hepatoprotective effect might be correlated with its antioxidant and radical-scavenging effects.

Efek Ekstrak Sambiloto (Andrographis paniculata Nees) pada Ekspresi Telomerase dari Kanker Payudara Tikus yang Diinduksi dengan DMBA

ABSTRACT&#x0D; &#x0D; It has been well documented that chemical carcinogen, 7.12 dimethylbenz(a)anthracene (DMBA), plays a role in the incidence and growth of mammary cancer. Present study was designed to investigate the influence of Andrographis paniculata extract on telomerase activities on DMBA induced breast cancer in the female rat Sprague Dawley strain. DMBA-induced mammary cancer is a useful model to investigate the changes of epithelial cells that occur during mammary cancer progression. Mammary cancer model was induced 10 times twice a week by oral DMBA 20 mg/kg body weight. Mammary cancer occurred in 75 % animals nine weeks after oral administration of DMBA, it was represented with nodule on the mammary gland and the increasing of mammary gland volume compare with normal control F(1.8) = 731.711; p &lt; 0.001. This study was also designed to investigate the effect of Andrographis paniculata extract mammary carcinoma induced by DMBA. Administration of three different dose of Andrographis paniculata (100 mg/kg, 300 mg/kg and 1000 mg/kg) had statistically different with mammary gland volume of DMBA treated rat F (4.17) = 92.777; p&lt;0.05. So, Andrographis paniculata has significant effect on the treatment of DMBA-induced mammary carcinoma. The Epithelial cells were harvested on day 90 and stained with routine histology staining, hematoxylineosin, for morphological qualitative analysis, immunohistochemical examination. The lesions observed from the removed samples ranged widely from benign to malignant. The results showed that DMBA induce cell proliferation, nuclear irregularities, and numerous mitoses and induced cell necrosis. The effect of Andrographis paniculata inhibits cell proliferation and induces apoptosis in cancer cells. On immunohistochemical examination, it shows that Andrographis paniculata can stimulate of telomerase enzyme.&#x0D; &#x0D; Key word: Andrographis paniculata, DMBA, mammary cancer, cell proliferation&#x0D; &#x0D; &#x0D; ABSTRAK&#x0D; &#x0D; Telah dilakukan penelitian efek ekstrak sambiloto (Andrographis paniculata Nees) pada ekspresi telomerase terhadap kanker payudara tikus betina (Sprague dawley) yang diinduksi dengan 7,12 dimethylbenz(a)anthracene (DMBA) menggunakan metode imunohistokimia. Diketahui model kanker payudara dengan induksi DMBA untuk menginvestigasi perubahan dari sel epitel yang terjadi selama prorses karsinogenesis kanker payudara. Pemberian ekstrak sambiloto pada tikus yang mengalami kanker payudara menyebabkan penurunan volume tumor dan ditinjau dari aspek hispatologi dan imunohistokimia adanya ekstrak sambiloto menyebabkan penghambatan proliferasi sel, penurunan ekspresi telomerase dan meningkatkan apoptosis.&#x0D; &#x0D; Kata Kunci : Andrographis paniculata,DMBA, kanker payudara, proliferasi sel&#x0D;

곰피 추출물이 난소를 절제한 흰쥐의 혈액 유동성 및 혈중 지질함량에 미치는 영향

Estrogen deficiency in peri- and postmenopausal women results in variety of neurovegetative, psychic and somatic symptoms, and may contribute to severe diseases within the aged female population. Ecklonia stolonifera (ES) is an edible brown algae traditionally used in fishery towns in Far East Asia. This study was performed to investigate the effects of ES extracts on blood flow and serum lipid concentration in ovariectomized rats. Weight-matched female Sprague-Dawley strain rats were assigned to four groups. Three groups were surgically ovariectomized (OVX). The fourth group was sham operated. Rats were randomly assigned to the following groups: sham-operated rats (Sham), ovariectomized control rats (OVX-CON), ovariectomized rats supplemented with ES extract at 50 mg/kg bw/day (OVX-ES50) and ovariectomized rats supplemented with ES extract at 200 mg/kg bw/day (OVX-ES200). Serum total cholesterol and triglyceride contents decreased in the sham group compared to the OVX-CON group. Six weeks feeding of ES extract resulted in a significant (p

Properties of nanopowdered chitosan and its cholesterol lowering effect in rats

This study was carried out to compare the properties of nanopowdered chitosan (NPC) to commercially powdered chitosan (CPC) and examine the effect of NPC on serum and liver cholesterol lowering in rats. Twentyfour male rats of Sprague-Dawley strain were blocked into 3 groups and were raised for 8 weeks. High cholesterol diet, 2% CPC, or 2% NPC were given to 3 groups. NPC reduced total cholesterol by 46.6% and CPC reduced it by 18.6%. NPC also significantly reduced low density lipoprotein (LDL)-cholesterol by 55.7%, while CPC reduced by 36.8%. High density lipoprotein (HDL)-cholesterol content was increased more with NPC by 16.5% than with CPC by 9.6%. Triacylglycerol content was also decreased significantly by 42.8% with NPC, while reduced by 22.5% with CPC. The present study indicated that NPC feeding reduced total and LDL-cholesterol and triacylglycerol contents and increased HDL-cholesterol content.

The differential expression of male sexual behavior in the Lewis, Fischer and Sprague-Dawley rat strains

Several indices of sexual behavior were characterized for male rats of the Lewis (LEW), Sprague-Dawley (SD) and Fischer (F344) strains. Males were permitted access to a receptive female of their own strain for five 50-min sessions every fifth day. LEW males emitted longer latencies (first mount, intromission, ejaculation and post-ejaculatory interval) and lower frequencies (mounts, intromissions, ejaculations, intromission ratio) relative to F344 males, with the SD strain in general, lying intermediate. Following this assessment, males of each strain were randomly assigned to females of their own or another strain to ascertain whether differences were due to differential female receptivity. Although there were no significant differences during this phase indicative of differential receptivity, the sample size may preclude a definitive interpretation of such results. The data were discussed in the context of other behavioral differences between the strains and the possible neurobiological mechanisms underlying these differences.

Moringa oleiferaPrevents Selenite-Induced Cataractogenesis in Rat Pups

The aim of this study was to investigate the protective effects of the flavonoid fraction of Moringa oleifera leaves (FMO) on selenite cataract in vivo. Rat pups of Sprague-Dawley strain initially weighing 10–12 g on day 8 were used for the study and grouped as control (G I), selenite induced (G II), and FMO treated (G III). The rat pups in G II and G III received a single subcutaneous injection of sodium selenite (4 µg/g body weight) on day 10 and G III was administered with FMO (2.5 µg/g body weight) from day 8 to 15. Cataract was visualized from day 16. The development of cataract was assessed and rat lenses were analyzed for the activities of antioxidant enzymes (superoxide dismutase and catalase), generation of reactive oxygen species, reduced glutathione, protein oxidation, and lipid peroxidation. FMO was subjected to in vitro antioxidant assays (2,2-diphenyl-picrylhydrazyl and superoxide scavenging assays). The total phenolic content of FMO was 4.4 mg of catechin equivalent/g dried plant material. The extract showed remarkable activity on 2,2-diphenyl-picrylhydrazyl (IC50 36 µg/mL) and in superoxide radical (IC50 33.81µg/mL) scavenging assays. FMO effectively prevented the morphological changes and oxidative damage in lens. FMO maintained the activities of antioxidant enzymes and sulfhydryl content and prevented reactive oxygen species generation and lipid peroxidation. FMO was effective in preventing cataractogenesis in selenite model by enhancing the activities of antioxidant enzyme, reducing the intensity of lipid peroxidation, and inhibiting free radical generation.

Efek Hepatoprotektif Infus Daun Sukun (Artocarpus altilis (Park) Fsb) Terhadap Kerusakan Hati Tikus yang Diinduksi dengan Karbon Tetraklorida

Breadfruit leaves (Artocarpus altilis (Park.) Fsb.) are used as traditional medicine intreatment of liver diseases. This study aimed to figure out the hepatoprotective effectof breadfruit leaves infusion in carbon tetrachloride-induced liver damage in malealbino rats. The study used 25 male albino rats of Sprague-Dawley strain, which weredivided randomly into five groups. Group I (normal control group) and group II(carbon tetrachloride-induced control group) only received 0,5% carboxymethylcellulose(CMC) solution. Group III-V received different dose of breadfruit leaves infusionfor seven days respectively, which were 13,5 g/kgBW (dose 1), 27 g/kg BW (dose2) and 54 g/kg BW (dose 3). On 7th day, all groups, excepted the normal group, wereinduced by 0,4 ml/kgBW dose of carbon tetrachloride perorally two hours after the lastbreadfruit leaves infusion given. Parameters of liver damage were estimated by measuringthe activity of plasma alanine aminotransferase (ALT), the concentration oflipid peroxide in liver, and the concentration of lipid peroxide in plasma. The resultsof ANOVA (pl0,05) demonstrated that breadfruit leaves infusion at a dose of 54 g/kgBW (dose 3) consumed for seven days respectively before 0,4 ml/kgBW dose ofcarbon tetrachloride-induced had hepatoprotective effect estimated by the activity ofplasma ALT and the concentration of lipid peroxide in liver.

Effect of Ardhabilva Kvatha Curna, an ayurvedic formulation, on liver and kidney function parameters of rat plasma after chronic administration

Ardhabilva Kvatha Curna (ADR), a widely used Ayurvedic formulation of Bangladesh, is the preparation of five important medicinal plants. In the present study, the liver and kidney function parameters of rats’ plasma were studied after chronic administration of ADR usually used in the treatment of Malabandha (obstructed feces). The animal used was albino rats (Rattus novergicus: Sprague-Dawley strains) and the drug was administered per oral route at a dose of 40 ml/kg body weight, once daily, up to 41 days for all the experiments. Forty rats, equally of both sexes, were randomly grouped into four where one male and one female group were used as control and other groups were used as test. In both of the male and female rats, there was a statistically very high significant increase in Bilirubin and Creatinine (p=0.001***). Except ALP and total protein, the other parameters that demonstrates liver function also increased significantly in both male and female rats as sGOT (male, p=0.283, female, p=0.029*), sGPT (male, p=0.028*, female, p=0.008**). A decreased concentration of both ALP and total protein was observed in both male and female rats and it was not statistically significant. The increase in albumin content was statistically very high significant in both sexes of the animal (p=0.001***). A decreasing trend of both Urea and Uric acid content was noticed in male and female rats and incase of female rats, it was statistically significant (p=0.038* and p=0.048* respectively).

Paternal genetic contribution influences fetal vulnerability to maternal alcohol consumption in a rat model of fetal alcohol spectrum disorder.

BackgroundFetal alcohol exposure causes in the offspring a collection of permanent physiological and neuropsychological deficits collectively termed Fetal Alcohol Spectrum Disorder (FASD). The timing and amount of exposure cannot fully explain the substantial variability among affected individuals, pointing to genetic influences that mediate fetal vulnerability. However, the aspects of vulnerability that depend on the mother, the father, or both, are not known.Methodology/Principal FindingsUsing the outbred Sprague-Dawley (SD) and inbred Brown Norway (BN) rat strains as well as their reciprocal crosses, we administered ethanol (E), pair-fed (PF), or control (C) diets to the pregnant dams. The dams' plasma levels of free thyroxine (fT4), triiodothyronine (T3), free T3 (fT3), and thyroid stimulating hormone (TSH) were measured to elucidate potential differences in maternal thyroid hormonal environment, which affects specific aspects of FASD. We then compared alcohol-exposed, pair fed, and control offspring of each fetal strain on gestational day 21 (G21) to identify maternal and paternal genetic effects on bodyweight and placental weight of male and female fetuses.ConclusionsSD and BN dams exhibited different baseline hypothalamic-pituitary-thyroid function. Moreover, the thyroid function of SD dams was more severely affected by alcohol consumption while that of BN dams was relatively resistant. This novel finding suggests that genetic differences in maternal thyroid function are one source of maternal genetic effects on fetal vulnerability to FASD. The fetal vulnerability to decreased bodyweight after alcohol exposure depended on the genetic contribution of both parents, not only maternal contribution as previously thought. In contrast, the effect of maternal alcohol consumption on placental weight was consistent and not strain-dependent. Interestingly, placental weight in fetuses with different paternal genetic contributions exhibited opposite responses to caloric restriction (pair feeding). In summary, these novel findings demonstrate both maternal and paternal genetic contributions to in utero vulnerability to alcohol, refining our understanding of the genetically-based heterogeneity seen in human FASD.

The differential expression of male sexual behavior in the Lewis, Fischer and Sprague‐Dawley rat strains

Lewis (LEW) and Fischer (F344) rats differ markedly in reactivity to drugs of abuse and mesolimbic dopamine activity, and interestingly sexual behavior is thought to be mediated in part by some common substrates. The following experiment examined sexual behavior of these strains (and outbred Sprague‐Dawley (SD) rats) to assess possible strain differences. Males were given repeated access to a receptive female of their respective strain during which sexual behavior was coded. Males were then exposed to a receptive LEW, F344 or SD female to assess if male behavior was a function of female receptivity. LEW males exhibited fewer mounts and intromissions (frequency and/or percent of subjects) than the F344 and SD strains (which never differed). Latency to first mount or intromission was similar for the F344 and SD strains but both were shorter than the LEW males (an index of sexual motivation). Ejaculation frequency and percent of subjects displaying ejaculation were different among strains (F344&gt; SD&gt;LEW). No LEW male ever ejaculated. For all males, there was no significant change in mounts, intromissions or ejaculations when given access to females of different strains, indicating the initial differences were not a result of strain differences in receptivity. These findings are consistent with a growing literature describing strain differences in motivated behaviors.Supported by a Mellon Foundation grant to ALR.

Uji Efek Antiartritis Ekstrak Etanol 80% Kulit Buah Delima Merah (Punica granatum L) Terhadap Udem Pada Telapak Kaki Tikus Putih Jantan yang diinduksi oleh Complete Freund’s Adjuvant

Rheumatoid arthritis is a chronic inflammatory disease that can degrade the qualityof patient survival. Conventional treatments of this disease have potentially dangerousside effects. Therefore, many patients are turning to alternative medicine usingmedicinal herbs, one of which is the fruit of Punica granatum L. The aim of thisresearch was to determine antiarthritis effect of 80% ethanolic extract of Punica granatumL. fruit peel which had been given orally on 17-30th day based on decreased edemavolume and percentage indexes of arthritis. The method was adjuvant induced arthritisby using the complete freundrs adjuvant 0,1 mL by subplantar and allowed toarthritis until day 16. The animals test were used 33 male rats of Sprague Dawleystrain that were divided into six groups: normal control, positive control, negativecontrol, and three groups had received suspension of 80% ethanolic extract of Punicagranatum L. fruit peel in 0,5% CMC at doses 20, 40, and 80 mg/200 g body weight.The Edema volume was measured by pletismometer on days 17, 20, 23, 26, 29, 31and indexes of arthritis determined on days 17 and 31. The Results showed that theywere not significant difference in the decreased edema volume and the percentageindexes of arthritis, although the percentage inhibition of edema elevated with increasingdose.

오징어 부산물이 혈액 유동성 및 혈중 지질 농도에 미치는 영향

Menopause increases the onset of hypertension and heart disease. Whereas it increases the blood LDL-cholesterol, triglyceride and total-cholesterol levels, the HDL-cholesterol concentration is reduced. Accordingly, we examined the effect of internal organs of Todarodes pacificus (IOT) on improvement in blood flow ability and changes in serum lipid content by using ovariectomized rats. For this study, the following four groups of 9-week-old Sprague-Dawley strain female rats were evaluated over 6 weeks: normal rats (SHAM), ovariectomized rats (CON) and ovariectomized rats that were treated with IOT extracts. Ovary removal promoted platelet aggregability. However, IOT administration in the CON group after ovary excision resulted in a hinderance of coherence. The blood vessel passing time of ovariectomized rats was slower than the SHAM group. But the blood flow ability, which was slowed down for ovary removal, was improved by IOT administration. Serum triglyceride levels were significantly reduced by IOT administration. Moreover, blood HDL-cholesterol levels were reduced by ovary removal. However, IOT administration after ovary excision significantly increase HDL-cholesterol levels. The biological activity of IOT could be confirmed from these results. Moreover, IOT can be used in the development of functional foods which are meant to improve blood circulation and anti-platelet aggregation function. According to these results, we could know that IOT improved blood flow and anti-platelet aggregation. Therefore, it is expected that IOT can be used for the development of functional foods.

Early predictors of cardiac decompensation in experimental volume overload

In humans, volume overload (VOL) increases the risk of sudden cardiac death, but there is also important inter-individual variability, presumably because of differences in genetic backgrounds. Although VOL has rapid effects on myocardial properties, it is not known to which extent the severity of these early responses correlate with the effect of sustained VOL on mortality. In order to test this question, we induced VOL in male rats from two genetically distinct strains [i.e., Sprague-Dawley (SD) and Wistar Kyoto-derived Hyperactive (WKHA) rats] by creating a surgical aorto-caval fistula (ACF). Only 36% of SD rats remained alive after 39 weeks of ACF, in contrast to 82% of the operated WKHA rats. We also monitored myocardial hemodynamic function, mitochondrial properties, left ventricular (LV) morphology and LV wall diastolic properties at different times ranging from 2 to 12 weeks after either ACF or sham surgery. ACF had a rapid impact on the LV walls of both rat strains, but the only variables that were affected to a greater extent in the mortality-prone SD strain were normalized LV weight, LV cavity area, and myocardial wall stiffness. In contrast, there were only marginal strain-related differences in the way ACF affected hemodynamic and mitochondrial functions. Thus, while early morphologic responses of LV walls to ACF (along with their downstream consequences on myocardial diastolic wall stress) correlated well with strain-dependent differences in late mortality, other functional changes showed no predictive effects. Close monitoring of early changes in cardiac geometry (as well as new methods to analyze myocardial diastolic strain) might, therefore, be helpful to further improve risk stratification in humans with volume overload cardiopathies.

Effect of etoricoxib, a cyclooxygenase-2 selective inhibitor on aberrant crypt formation and apoptosis in 1,2 dimethyl hydrazine induced colon carcinogenesis in rat model.

Etoricoxib, a second generation selective cyclooxygenase-2 (COX-2) inhibitor had been studied for the chemopreventive response at its therapeutic anti-inflammatory dose in 1,2-dimethylhydrazine (DMH) induced colon carcinogenesis in rat model. Eight to ten weeks old male rats of Sprague-Dawley strain were divided into four groups. While group 1 served as control and received the vehicle of the drugs, group 2 and 3 were administered freshly prepared DMH in 1mM EDTA-saline (pH 7.0) (30 mg/kg body wt/week, subcutaneously). Group 3 was also given a daily treatment of etoricoxib (0.6 mg/kg body wt orally) while the group 4 received the same amount of etoricoxib only, prepared in 0.5% carboxymethyl cellulose. Animals were sacrificed at the end of 6 weeks, body weight recorded and the colons were subjected to macroscopic and histopathological studies. The maximum number of raised mucosal lesions called the multiple plaque lesions (MPL) were found in the DMH group which significantly reverted back in the DMH + etoricoxib group, while very few MPLs were recorded in the control and etoricoxib only group. Similarly, the number of aberrant crypt foci (ACF), the point of future carcinogenic growth, was recorded more in the DMH group and significantly less in the DMH + etoricoxib group. The histopathological analysis showed the presence of severe hyperplasia, occasional dysplasia and aggregates of lymphoid cells in the localized regions. Etoricoxib group showed near normal histological features with the crypt architecture and the surrounding stromal tissue remaining intact. To ascertain the molecular mechanism of such anti-carcinogenic features the colonocytes were isolated and studied in primary culture for the evidence of apoptosis by fluorescent staining and genotoxic changes by single cell gel electrophoresis assay (comet assay) which shows that the DMH treated animals produced much less apoptotic nuclei but more comet producing cell, while these features were reverted back with the etoricoxib treatment. The cytoplasmic expression of COX-2 protein was studied in paraffin sections of the colon by immunohistochemistry with COX-2 specific antibody which showed a very high presence of this inducible enzyme with the DMH group while in all other groups of animals it was not visible or weekly expressed. The anti-inflammatory effect of the drug, etoricoxib was also validated by a carrageenan-induced inflammation in rat model which showed an extremely high anti-inflammatory response within the dose range used in the present study. Also the growth profile of all the animals remained the same throughout the six week period of the investigation as there was no change in the body weight. It appears that apoptosis remains the dominant anti-proliferative end effect of this drug, mediated by an inhibition of the proinflammatory COX-2 isoform although further molecular probings are needed to arrive at a conclusive agreement in favor of the chemoprotective use of such drugs in colon cancers.

Structural diversity of nucleoside phosphonic acids as a key factor in the discovery of potent inhibitors of rat T-cell lymphoma thymidine phosphorylase

Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC 50 values below 1 μM were selected. Out of them, four compounds strongly inhibited the enzyme with IC 50 values lying in a range of 11–45 nM. These most potent compounds might be bi-substrate analogues.

Toll-Like Receptor mRNA Expression Is Selectively Increased in the Colonic Mucosa of Two Animal Models Relevant to Irritable Bowel Syndrome

BackgroundIrritable bowel syndrome (IBS) is largely viewed as a stress-related disorder caused by aberrant brain-gut–immune communication and altered gastrointestinal (GI) homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs) are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stress-induced IBS-like symptoms.Methodology/Principal FindingsIn this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensivity; the stress-sensitive Wistar-Kyoto (WKY) rat and the maternally separated (MS) rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains.ConclusionsThese data suggest that both early life stress (MS) and a genetic predisposition (WKY) to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS.