11-dehydrocorticosterone and Disease-Models--Animal

Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production.. Rats were exposed to PSS for ten days. Thirty days later, the rats' anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex.. Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the. Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.

Topics: Adrenal Glands; Animals; Case-Control Studies; Chromatography, High Pressure Liquid; Corticosterone; Desoxycorticosterone; Disease Models, Animal; Phenotype; Rats; Stress Disorders, Post-Traumatic; Stress, Psychological; Zona Fasciculata

11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) is a microsomal NADPH-dependent oxidoreductase which elevates intracellular concentrations of active glucocorticoids. Data obtained from mouse strains with genetically manipulated 11HSD1 showed that local metabolism of glucocorticoids plays an important role in the development of metabolic syndrome. Tissue specific dysregulation of 11HSD1 was also found in other models of metabolic syndrome as well as in a number of clinical studies. Here, we studied local glucocorticoid action in the liver, subcutaneous adipose tissue (SAT) and skeletal muscles of male and female Prague hereditary hypertriglyceridemic rats (HHTg) and their normotriglyceridemic counterpart, the Wistar rats. 11HSD1 bioactivity was measured as a conversion of [(3)H]11-dehydrocorticosterone to [(3)H]corticosterone or vice versa. Additionally to express level of active 11HSD1 protein, enzyme activity was measured in tissue homogenates. mRNA abundance of 11HSD1, hexoso-6-phosphate dehydrogenase (H6PDH) and the glucocorticoid receptor (GR) was measured by real-time PCR. In comparison with normotriglyceridemic animals, female HHTg rats showed enhanced regeneration of glucocorticoids in the liver and the absence of any changes in SAT and skeletal muscle. In contrast to females, the glucocorticoid regeneration in males of HHTg rats was unchanged in liver, but stimulated in SAT and downregulated in muscle. Furthermore, SAT and skeletal muscle exhibited not only 11-reductase but also 11-oxidase catalyzed by 11HSD1. In females of both strains, 11-oxidase activity largely exceeded 11-reductase activity. No dramatic changes were found in the mRNA expression of H6PDH and GR. Our data provide evidence that the relationship between hypertriglyceridemia and glucocorticoid action is complex and gender specific.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Carbohydrate Dehydrogenases; Corticosterone; Disease Models, Animal; Female; Glucocorticoids; Hypertriglyceridemia; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Rats; Rats, Wistar; Receptors, Glucocorticoid; Sex Factors; Subcutaneous Fat

Tuberculosis has a staggering influence on world health, resulting in nearly 2 million deaths per year. The influence of glucocorticoids during Mycobacterium tuberculosis infection has been under investigation for decades; however, the identity of mycobacterial factors and the mechanism by which glucocorticoids are tissue specifically regulated to influence immune function during acute granuloma formation are unknown.. One factor implicated in initiating immunopathology during M. tuberculosis infection is trehalose-6,6'-dimycolate (TDM), a glycolipid component of the mycobacterial cell wall. Intravenous administration of TDM causes inflammatory responses in lungs of mice similar to M. tuberculosis infection and has been used as a successful model to examine proinflammatory regulation and early events involved in the manifestation of pathology.. IL-6, IL-1alpha and TNF-alpha mRNA and protein peaked during the initiation of granuloma formation. Pulmonary corticosterone levels were elevated when the proinflammatory response was greatest, dropping to half of that upon the establishment of granuloma pathology on day 7. It is hypothesized that once corticosterone reaches the site of inflammation, the enzymes 11beta-hydroxysteroid dehydrogenases (11betaHSDs) can influence bioavailability by interconverting corticosterone and the inert metabolite 11-dehydrocorticosterone. RT-PCR demonstrated that pulmonary 11betaHSD type 1 mRNA decreased 4-fold and 11betaHSD type 2 (11betaHSD2) mRNA expression increased 2.5-fold on day 3 after injection, suggesting that corticosterone regulation in the lung, specifically the reduction of active corticosterone by 11betaHSD2, may influence the progression of granuloma formation in response to the mycobacterial glycolipid.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Animals; Cord Factors; Corticosterone; Cytokines; Disease Models, Animal; Down-Regulation; Female; Granuloma, Respiratory Tract; Immune Tolerance; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; RNA, Messenger; Tuberculosis, Pulmonary; Up-Regulation

Pro-inflammatory processes are counteracted by anti-inflammatory factors such as glucocorticoids. The response of target cells to glucocorticoids depends on several factors including prereceptor modulation of glucocorticoid signals via local glucocorticoid metabolism. This is determined by two isoforms of 11beta-hydroxysteroid dehydrogenase (11betaHSD); 11betaHSD1 operates in vivo as a reductase converting inactive 11-oxo glucocorticoids to active glucocorticoids cortisol or corticosterone, whereas 11betaHSD2 catalyses oxidation of active glucocorticoids to their inactive 11-oxo derivatives. The aim of this study was to investigate the changes in local metabolism of glucocorticoids and in the expression of 11betaHSD1 and 11betaHSD2 mRNA during colonic inflammation.. Acute colitis was induced by intracolonic administration of 2,4,6-trinitrobenzenesulphonic acid (TNBS) or by drinking a dextran sodium sulphate (DSS) solution. Metabolism of glucocorticoids was measured in tissue fragments in vitro and 11betaHSD1 and 11betaHSD2 mRNA abundance was quantified using real-time RT-PCR one week after administration of TNBS and 10 days after drinking the DSS solution.. In both models of inflammatory bowel disease we observed down-regulation of corticosterone oxidation to 11-dehydrocorticosterone by 64% (TNBS) and 53% (DSS) and reciprocal stimulation of reduction of 11-dehydrocorticosterone to corticosterone by 83% and 54%, respectively. A similar pattern was observed at the level of mRNA; 11betaHSD1 mRNA was significantly higher (TNBS: increase by 660%; DSS: increase by 760%) and 11betaHSD2 mRNA lower (TNBS: decrease by 85%; DSS: decrease by 60%) during inflammation.. Colitis induces local glucocorticoid activation from 11-oxo steroids and decreases glucocorticoid inactivation; i.e. inflammation increases local tissue ratio of active and inactive glucocorticoids. The results indicate that the changes in local metabolism of glucocorticoids could contribute to the control of an overshoot of inflammation processes in the colon.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Animals; Colitis, Ulcerative; Corticosterone; Crohn Disease; Dextran Sulfate; Disease Models, Animal; Male; Rats; Rats, Wistar; RNA, Messenger; Trinitrobenzenesulfonic Acid

Studies in normotensive rats showed that excessive fetal exposure to maternal glucocorticoids retards growth and programs hypertension in later life. This excessive exposure is proposed to occur due to a reduction of the placental barrier to maternal glucocorticoids that is provided by 11beta-hydroxysteroid dehydrogenase (11betaHSD). To assess the possible alterations of glucocorticoid placental barrier in two genetic models of hypertension - spontaneously hypertensive (SHR) and Dahl salt-sensitive rats (DS) and their normotensive counterparts Wistar-Kyoto (WKY) and Dahl salt-resistant rats (DR)-we performed real-time reverse transcriptase-polymerase chain reaction analysis and bioactivity measurements of placental 11betaHSD in the last third of gestation. Whereas 11betaHSD2 mRNA expression was not different among the investigated strains, 11betaHSD1 mRNA abundance was 2.4 times higher in WKY than in SHR and 9.6 times higher in DS than in DR placentae. The 11betaHSD2 activity studies performed in placental homogenates revealed activity that did not differ among the strains. Concomitant with 11betaHSD1 mRNA expression 11-oxoreductase activity was clearly evident in all strains and was higher in WKY and DS rats than in SHR and DR, respectively. Nevertheless, the net 11betaHSD activity of tissue fragments (11beta-dehydrogenase minus 11-oxoreductase) was tended toward dehydrogenase action, ie, toward corticosterone inactivation and was significantly lower in DS than in DR rats. The 11beta-dehydrogenase/11-oxoreductase ratio was less than 2:1 in SHR and WKY rats, whereas this ratio was 9:1 in DR and 4.5:1 in DS rats. These data suggest that the placental glucocorticoid barrier is not decreased in SHR rats in comparison with normotensive WKY but is lower in DS than in DR counterparts. It cannot be excluded, therefore, that the placental glucocorticoid barrier in Dahl rats influences the pathways that might lead to the sensitivity of blood pressure to high salt intake in later life.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Actins; Animals; Blood Pressure; Corticosterone; Disease Models, Animal; Female; Hydroxysteroid Dehydrogenases; Hypertension; Isoenzymes; Models, Cardiovascular; NADP; Organ Size; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Glycyrrhetinic acid (GA) inhibits 11beta-hydroxysteroid dehydrogenase and increases the levels and thus the action of endogenous glucocorticoid. We considered that GA could be used effectively for treatment of autoimmune diseases that have been treated by synthetic glucocorticoids. In this report, we demonstrated that GA delayed the development of autoimmune disease in spontaneously autoimmune strain MRL lpr/lpr (referred to as lpr) mice. GA was administered via drinking water at approximately 5 mg/kg/day for 170 days. An increase of urine protein levels in the mice treated with GA was delayed as compared to the control mice. After GA treatment began, urinary protein levels in the GA-treated mice were found to be significantly lower than vehicle-treated mice (p<0.05) between days 18 to 50. At 3 weeks of GA treatment serum IgG levels were lowered significantly in comparison with the control mice (p<0.03). In this circumstance, 11beta-HSD activities in liver and kidney were significantly inhibited by GA treatment (p<0.03, p<0.04 respectively). Concentration of corticosterone and dehydrocorticosterone in liver significantly increased after 3 weeks of GA treatment (p<0.02, p<0.01 respectively). In contrast to the local tissue levels of corticosteroids, the serum concentration of dehydrocorticosterone significantly decreased with GA treatment (p<0.02). These data suggest that GA could modify the local and systemic homeostasis of steroid metabolism in lpr mice. We concluded that the continuous treatment of GA is able to retard the development of autoimmune disease by suppressing urinary protein excretion and serum IgG levels in lpr mice. Modulation of local tissue levels as well as serum levels of corticosteroid by GA may thus be implicated in the therapeutic efficacy of GA.

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Administration, Oral; Animals; Autoimmune Diseases; Body Weight; Corticosterone; Disease Models, Animal; Enzyme Inhibitors; Glycyrrhetinic Acid; Hydroxysteroid Dehydrogenases; Kidney; Liver; Male; Mice; Mice, Inbred MRL lpr; Organ Size; Water Supply