Subcutaneous Administration Of Dexamethasone Research Articles

Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway

Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.

Suppressive effect of dexamethasone on murine Th9 cell-mediated nasal eosinophilic inflammation.

BackgroundTh9 cells have been implicated in the development of allergic inflammation, though its contribution to allergic rhinitis and the effect of steroid on Th9 cell-mediated nasal responses are unclear.ObjectiveIn this study, allergen-induced nasal inflammatory responses and their steroid responsiveness were investigated in ovalbumin (OVA)-specific Th9 cell-transferred mice.MethodsBALB/c mice were transferred with in vitro-differentiated Th9 cells and challenged by intranasal injection of OVA with or without subcutaneous administration of dexamethasone (Dex). Then, the infiltration of inflammatory cells in the nasal mucosa and nasal hyperresponsiveness (NHR) was assessed.ResultsThe significant NHR accompanied by nasal infiltration of eosinophils as well as allergen-specific T cells was induced in Th9 cell-transferred mice upon allergen challenge. These responses were strongly suppressed by the treatment with Dex.ConclusionThe participation of Th9 cells in the pathogenesis of allergic rhinitis was suggested.

THE EFFECT OF MELATONIN ON THE ENERGY METABOLISM IN HEART OF DIABETIC RATS

The aim of this study was to determine the effect of melatonin on activity of pyruvate kinase (PK) and lactate dehydrogenase (LDH) in the heart tissue and on the activity of succinate dehydrogenase (SDG) and H+-ATPase in mitochondria of cardiomyocytes of rats with dexamethasone diabetes. Methods. The research was performed in compliance with the Rules of the work with test animals (1977) and the European Convention on the Protection of Vertebrate Animals used in experiments and other scientific purposes (18 March 1986). The experiments were carried out on 36 sexually mature male albino rats with the body mass 0.18 – 0.20 kg. The animals were divided into 3 groups:1) control group; 2) group with diabetes mellitus DM (BG level ≥ 8.0 mmol/l); 3) diabetic animals which were injected with melatonin. Melatonin (“Sigma”, USA) was injected intraperitoneally in a dose of 10 mg/kg of body weight daily over 13 days. Dexamethasone diabetes was evoked by daily subcutaneous administration of dexamethasone (solution for injection 4 mg / ml, KRKA, Slovenia) at a dose of 0.125 mg / kg body weight for 13 days (O.V. Stefanov, 2001). The mathematical model of the insulin-glucose correlation by the Homeostasis Model Assessment (HOMA) was used to evaluate the insulin resistance in the animals (D.R.Matthews et al., 1985). The blood was taken from the tail vein to evaluate the BG level using “OneTouchUltra” (“LifeScan”, USA). The rats were sacrificed on the 14th day of the experiments in accordance with the ethical treatment of animals. 5% homogenate was prepared from cold-isolated rat hearts on chilled 50 mM Tris-HCl buffer (pH = 7.4) with sucrose. Mitochondria were isolated by differential centrifugation. Enzyme activities in the mitochondrial fraction was determined by: succinate dehydrogenase (SDG) according to the method of Eshchenko N.D. et al. (1992), H + -ATP-ase - for Gabibiv M.M. (1986). Serum insulin content was determined using an automatic immunochemiluminescent analyzer (Snibe Co., Ltd, PRC) using a Maglumi test kit. The insulin resistance index (HOMA-IR) was calculated by the formula: HOMA-IR = (glucose (mmol / l) • insulin (mcU / ml)) / 22.5. To determine the enzymes activities by standart methods, heart muscle tissue was quickly removed, rinsed in saline, blotted, weighed and homogenized. Then the homogenate (5% in ice-cold 0.25 mM tris-HCl-buffer) was ultracentrifugated (10 min at 1500r/min) and the supernatant was used for measurements. Statistical analysis was performed using Statistica 10 (StatSoft Inc). Prior to analysis, Shapiro-Wilk test was used to assess the normality of the group data. According to the criterion, the samples distributions differed from normal distribution. Given these, use of the Mann-Whitney test was considered sufficient for valid conclusions to be made. Differences were considered to be statistically significant when P ≤ 0.05. Results. In the blood of all diabetic rats on the 14th day the glucose content exceeded 8.9 mmol / l, and the HOMA-IR index increased 7 times. According to results, we have obtained the activity of PK in the heart tissue of diabetic animals was 55% less than in control group. It can be explained by low uptake of glucose from the blood by heart muscle tissue in conditions of insulin resistance. Reduced glucose uptake by peripheral tissues, in turn, leads to a reduced rate of glucose metabolism. That means now substrate for next catabolic changes in glycolysis. The activity of LDH increases by 32% in the heart muscles of diabetic rats compared with the control values. We have found out that the activity of PK and LDH has become normalized by the introducing of melatonin in dose of 10 mg/kg of body weight. In the mitochondria of the animals with dexamethasone diabetes, the activity of SDG and H+ -ATPase is significantly lower than that in intact animals by 45 and 32%, respectively. Probably, melatonin enhances the uptake of glucose by heart muscles. The blood glucose content of diabetic rats, which were administered is not significantly different from that of the intact animals, and the HOMA-IR was 6.3 times lower than that of diabetic rats. The activity of SDG and H+-ATPase in the mitochondria of rats receiving both melatonin and dexamethasone does not differ from that of intact rats. Conclusion. A 14-day introduction of melatonin leads to a marked improvement of the state of carbohydrate metabolism as well as the energy metabolism in heart tissue that is accompanied by the normalization of the indices studied.

Investigation of hypoglycemic properties of ginger extract on type 2 diabetes mellitus experimental model, caused by dexamethasone

Topicality. In pharmacotherapy of type 2 diabetes mellitus and metabolic syndrome, whose complex of disorders develops against the background of insulin resistance, medicinal plants are used as an important prophylactic and therapeutic additon, which causes the urgency of developing new domestic anti-diabetic herbal medicinal products.Aim. To study the anti-hyperglycemic properties of the extract of ginger on the experimental model of type 2 diabetes induced by dexamethasone.Materials and methods. Type 2 diabetes mellitus was reproduced by subcutaneous administration of dexamethasone at a dose of 0.125 mg/kg to rats for 13 days. Antihyperglycemic effect was assessed on day 14 for the concentration of glucose and insulin in the blood serum and the insulin resistance index.Results and discussion. The results of the study showed that ginger extract in doses of 50 and 80 mg/kg had a pronounced antihyperglycemic effect, which, according to obtained results, is implemented due to its ability to improve the sensitivity of peripheral tissues to the action of insulin, and thus to reduce the manifestations of insulin resistance.The use of the extract of ginger in a dose of 80 mg/kg revealed the most pronounced correction of the parameters of carbohydrate metabolism. The severity of the anti-hyperglycemic effect of the extract of ginger at a dose of 80 mg/kg is comparable to the effect of harvesting Arfazetine.Conclusions. The obtained results justify the expediency of further studying the extract of ginger at a dose of 80 mg/kg as a promising antidiabetic agent.

Detection of Pneumocystis in the nasal swabs of immune-suppressed rats by use of PCR and microscopy

BackgroundDetection of Pneumocystis jiroveci colonization in lungs or oral samples due to high sensitivity of PCR methods results in undue treatment of patients without any symptoms of Pneumocystis pneumonia. The aim of the present study is to demonstrate Pneumocystis carinii in rats, immune suppressed by oral and subcutaneous administration of dexamethasone.Material/MethodsBlood, oral, nasal and eye swabs were collected prior to immune suppression and 2, 6, 12 weeks after administration of dexamethasone. Also, samples were collected from lung, heart, liver, kidney, diaphragm, brain, spleen, tongue, muscle, eye, intestine, and feces. Cysts and trophozoites were investigated in stained slides and MSG gene was detected by PCR.ResultsThe results showed that weight loss is significantly higher in rats administered oral dexamethasone (P<0.05). Microscopy was positive only in lungs of rats orally administered dexamethasone. PCR was positive in lungs and oral swabs of rats prior to the administration of dexamethasone. After the administration of dexamethasone, the MSG gene was detected in oral swabs, lungs, spleen, kidney and (for the first time) in nasal swabs. PCR was positive in nasal swabs during the second and sixth weeks of oral and subcutaneous administration of dexamethasone, respectively.ConclusionsPresence of P. jiroveci in nasopharyngeal aspirate, oropharyngeal wash, oral swab, induced sputum or BAL, and absence in nasal swab in a patient without symptoms of PCP may support clinician’s decision regarding colonization. Overall, detection of P. carinii in nasal swabs of rats by PCR demonstrated that nasal sampling can be used for the diagnosis of Pneumocystis pneumonia.

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The triglyceride and glucose lowering potential of the leaf extracts of Pterocarpus santalinoides was investigated in dexamethasone induced hyperlipidemia and insulin resistance in rats. Acute toxicity test was performed according to standard methods. An oral glucose tolerance test was carried out in the presence of the extracts in normal rats. Then, graded doses of aqueous and methanol extracts of P. santalinoides (AEPS and MEPS) were administered orally to rats in four groups, respectively, after a 12 h fast followed by subcutaneous administration of dexamethasone (10 mg/kg body wt). Rats in a fifth group received saline (5 ml/kg p.o) followed by dexamethasone (10 mg/kg body wt s.c) and served as positive control while a sixth group served as normal control. The period of extract and dexamethasone administration was 10 days. Acute toxicity test showed that the extract had an oral LD 50 > 5000 mg/kg in rats. Graded doses of aqueous and methanol extracts of P. santalinoides to glucose loaded normal rats resulted in significant lowering of blood glucose concentration which started at 90 min post-glucose load when compared with the 60 mine (peak) sample (p < 0.001) and also when compared with the negative control value at 90 min (p < 0.001). Administration of dexamethasone to fasted rats for 10 days resulted in hyperlipidemia and insulin resistance evidenced by the significant increase in mean glucose level (194.50 ± 9.87 mg/dl) and triglyceride level (268.75 ± 21.54 mg/dl) in the positive control when compared with the normal control with mean glucose and triglyceride concentrations of 64.00 ± 3.44 mg/dl and 100.00 ± 15.54 mg, respectively (p < 0.01; p < 0.001). Graded doses of the AEPS and MEPS significantly antagonized dexamethasone induced hyperlipidemia and insulin resistance in rats when compared with the positive control (p < 0.001) and the normal control, respectively (p < 0.05). The antagonistic potency of AEPS was dose dependent while that of the MEPS was not. The leaf extracts of P. santalinoides possess triglyceride and glucose lowering properties in dexamethasone induced hyperlipidemia and insulin resistance and could be of therapeutic value in the management of metabolic syndrome.

Use of Anti-Platelet-Endothelial Cell Adhesion Molecule-1 Antibody in the Control of Disease Progression in Established Collagen-Induced

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is expressed on the membrane of leukocytes and vascular endothelial cells. PECAM-1 has been shown to play an important role in the process of leukocyte transmigration in various animal models of acute inflammation. We investigated the role of PECAM-1 in the progression of arthritis by systemically administering anti-murine PECAM-1 monoclonal antibody, 2H8, to DBA/1J mice with collagen-induced arthritis (CIA). Subcutaneous administration of dexamethasone (0.5 mg/kg per 2 days) significantly reduced hindpaw swelling and the clinical score of established CIA. Intraperitoneal administration of 2H8 (0.25 mg/mouse per 2 days) significantly inhibited hindpaw swelling in a time-dependent manner. 2H8 also significantly prevented further deterioration in the clinical score, but failed to reverse joint destruction discernible at the histological level. Both dexamethasone and 2H8 inhibited body weight decrease by preventing the further development of arthritis. Histopathological assessment revealed that 2H8, as well as dexamethasone, inhibited inflammatory cell transmigration into the synovium of the hind paw joint and ameliorated synovitis and cartilage erosion. These results suggest that PECAM-1 plays an important role in the progression of CIA and that an inhibitor of PECAM-1 might have therapeutic value for clinical treatment of rheumatoid arthritis.

Glucocorticoid regulation of ornithine decarboxylase in the postnatal rat lung

Ornithine decarboxylase (ODC) is thought to play a critical role in pulmonary development. The purpose of this study was to characterize the effects of dexamethasone on ODC gene expression and enzyme activity in the lung of rat pups. Subcutaneous administration of dexamethasone (10 mg kg ) was shown to suppress ODC activity in 2-, 6- and 10-day-old rats for as long as 24 h after injection. In contrast, dexamethasone treatment stimulated liver ODC activity indicating that the inhibition of lung ODC is tissue specific. Contrary to expectation, the glucocorticoid enhanced lung ODC expression as indicated by an increased accumulation of ODC mRNA transcripts. The latter effect was associated with an heightened expression of c-myc and max mRNAs, the encoded proteins of which act as transactivators of the ODC gene. Dexamethasone did not alter lung levels of “antizyme” (AZ), an inducible protein that specifically promotes the degradation of the ODC protein enzyme. However, the lack of AZ induction does not necessarily mean that ODC degradation is not the mechanism for the decrease in lung ODC activity of dexamethasone-treated animals. The results obtained indicate that glucocorticoids can downregulate lung ODC activity, and that the effect is mediated by post-transcriptional rather than transcriptional mechanisms. These findings are consistent with the idea that endogenous glucocorticoids play an important role in the modulation of ODC activity and early pulmonary development.

Age-Related and Dexamethasone-Induced Changes in Cathepsins E and D in Rat Thymic and Splenic Cells

Age-related and dexamethasone (DEX)-induced changes in the cellular levels, distributions, and molecular forms of two distinct intracellular aspartic proteinases, cathepsin E (CE) and cathepsin D (CD), were investigated in rat thymus and spleen by immunohistochemical and quantitative analyses. In the thymus, CE was predominantly restricted to thymocytes and macrophage-like cells, whereas CD was associated mainly with the stromal cells. The increased thymic CE level observed in young rats up to 8 weeks of age was markedly decreased in aged rats (78–80 weeks of age), in accordance with the involution of the thymus, while there was little difference in the thymic CD level between young and aged rats. Subcutaneous administration of DEX also caused a marked decrease of the thymic CE level in response to the depletion of thymocytes. In contrast, a great accumulation of CD occurred in the thymic stromal cells after DEX treatment. Immunoblotting analyses revealed that CE in thymocytes isolated from young rats consisted predominantly of a 46-kDa proform which was greatly converted into a 42-kDa mature form in DEX-treated thymocytes. This conversion, however, was scarcely observed during the normal aging process. In the spleen, CE was also abundant in macrophage-like cells and lymphocytes and its level was not significantly changed between young and aged rats. However, DEX treatment caused a marked decrease of the splenic CE and CD levels in accordance with the depletion of the white pulp. Among the lymphoid cell types examined, splenic B cells were the most abundant in CE. The CE level in thymocytes and splenic T-cells was more than twice that in circulating lymphocytes. We concluded that CE is related to the process of activation-induced lymphocyte depletion.

Calcium-binding protein regucalcin mRNA expression in the kidney cortex is suppressed by saline ingestion in rats.

The effect of adrenalectomy (ADX) or saline ingestion, which is a hypertensive factor, on the expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats was investigated. The change of regucalcin mRNA levels was analyzed by Northern blotting using rat liver regucalcin complementary DNA (0.9 kb of open-reading frame). Regucalcin mRNA was expressed in the kidney cortex but not the medulla. Rats were adrenalectomized, and 48 h later they were sacrificed. ADX caused a reduction of regucalcin mRNA levels in the kidney cortex, suggesting that adrenal glands participate in the regulation of the mRNA expression. This reduction was not restored by the subcutaneous administration of dexamethasone with an effective dose (1 mg/kg body weight), which can stimulate kidney regucalcin mRNA expression. Regucalcin mRNA levels in the kidney cortex of rats were markedly suppressed by the ingestion of saline for 7 days. The ADX-induced decrease of renal cortex regucalcin mRNA levels was not appreciably restored by saline ingestion. Moreover, regucalcin mRNA levels in the kidney cortex of spontaneous hypertensive rats (SHR) were clearly decreased as compared with that of control (Wistar-Kyoto) rats. Meanwhile, calcium content in the kidney cortex was not significantly decreased by ADX or saline ingestion. The present study suggests that the expression of regucalcin mRNA in the kidney cortex of rats is suppressed by saline administration.

A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice.

Previously, a hypomorphic mutation in CD18 was generated by gene targeting, with homozygous mice displaying increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain, virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed hyperplasia of the epidermis, subcorneal microabscesses, orthohyperkeratosis, parakeratosis, and lymphocyte exocytosis, which are features in common with human psoriasis and other hyperproliferative inflammatory skin disorders. Repetitive cultures failed to demonstrate bacterial or fungal organisms potentially involved in the pathogenesis of this disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. Homozygous mutant mice on a (PL/J x C57BL/6J)F1 background did not develop the disease and backcross experiments suggest that a small number of genes (perhaps as few as one), in addition to CD18, determine susceptibility to the disorder. This phenotype provides a model for inflammatory skin disorders, may have general relevance to polygenic human inflammatory diseases, and should help to identify genes that interact with the beta2 integrins in inflammatory processes.