Single Administration Of Dexamethasone Research Articles

Molecular Response of Rabbit Menisci to Surgically Induced Hemarthrosis and a Single Intra-Articular Dexamethasone Treatment.

Anterior cruciate ligament reconstructive surgery can restore biomechanical stability, however, such surgery cannot reliably prevent the onset of post-traumatic osteoarthritis. The aim of this study was to elucidate the molecular response that occurs within the menisci following a surgical injury that allows bleeding into the joint space, and then to investigate the effect of dexamethasone (DEX) on this molecular response. Cell viability studies following acute controlled exposure to blood and blood plus DEX were also conducted. Forty-eight New Zealand white rabbits were randomly allocated into control, sham, surgical, and surgical + DEX groups (each group n = 6). Animals were sacrificed at 48 h and 9 weeks, and menisci were harvested. The messenger RNA (mRNA) expression levels for key inflammatory, and degradative proteins, as well as mRNA levels for autophagy pathway molecules were quantified, and statistically significant changes were described. Meniscal cell viability was calculated by incubating groups of medial and lateral menisci in autologous blood, or autologous blood plus DEX for 48 h (each group n = 4; total of eight medial and eight lateral menisci), and then conducting a histological live/dead assay. Results indicated a significant reduction in only medial meniscal cell viability when the tissue was exposed to blood in combination with DEX. A single administration of DEX following surgery significantly suppresses the elevated molecular expression for key inflammatory and degradative markers within menisci at 48 h and 9 weeks post-surgery. In vitro, autologous blood did not affect cell viability, but addition of DEX uniquely impacted the medial menisci. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2043-2052, 2019.

A single administration of dexamethasone may protect tibial plateau cartilage in a mechanically stable surgical model of post traumatic osteoarthritis

Purpose: An acute inflammatory phase follows an injury to the knee joint and initiates a cascade of biochemical events that can contribute to degeneration of the cartilage. Cartilage degeneration after injury is central in the development of posttraumatic osteoarthritis (PTOA) – a debilitating disease that is increasingly affecting active younger individuals. It is currently believed that inflammation following intra-articular bleeding from joint injuries could be a cause in the development of PTOA. To study the effects of inflammation alone within the joint, an injury model was developed in which tissue structures responsible for joint function and stability were not directly impacted. Preliminary evidence in this rabbit model of intra-articular bone injury, intended to simulate posttraumatic hemarthrosis, has shown what appears to be an acute inflammatory phase that resolves after surgery and yet still results in the development of significant PTOA. Therefore, we hypothesize that if insult to the joint increases the expression level of acute inflammatory mediators that expose the cartilage to injury then an intervention that inhibits acute inflammation (dexamethasone) will have positive outcomes on cartilage health within this rabbit bone injury model. Dexamethasone (dex) is a glucocorticoid with potent anti-inflammatory properties that has been widely adopted for clinical use (e.g. in the treatment of rheumatoid arthritis, asthma, and various cancers). Methods: Skeletally mature adult female rabbits aged 52 weeks (n = 18) were used in this study. Six animals were not subjected to any interventions and served as un-operated controls. The remaining 12 were all subjected to a femoral notch drill surgery following the guidelines of our institutional animal care facility. Of this group, six rabbits were treated with one intra-articular injection of Dex (0.5 mg/kg) at the time of surgery. As surgical controls, the remaining 6 animals were subjected to drill surgery, but did not receive any dexamethasone treatment. Animals were sacrificed at 9 weeks post surgery. Histological assessment was completed by two blinded observers using a modified Mankin protocol. qPCR was used to analyze the mRNA levels for select anabolic and catabolic molecules, and values were normalized to 18S mRNA. Kruskal-Wallis with Dunn’s multiple comparisons test were used to investigate treatment group differences (significance accepted at p ≤ 0.05). Results: Histological evaluations (Figure 1A) revealed that at 9 weeks post surgery the cartilage on the tibial plateaus of the drill animals was significantly more damaged than that of the un-operated controls and the animals that received the dex treatment after injury. There were no significant differences between the tibial plateau cartilage of the normal and drill + dex treatment groups, suggesting a positive role for dexamethasone. Furthermore, the mRNA analysis (Figure 1B) revealed that even a single dose of dexamethasone at the time of surgery, was sufficient to attenuate the expression of degradative proteinase matrix metalloproteinase 3 (MMP-3), proteoglycans such as versican and biglycan as well as anabolic marker collagen type II (Col-II) in tibial plateau cartilage. Conclusions: Even in the absence of severe biomechanical changes, the cartilage of the tibial plateau is subject to degeneration in this model. This strongly suggests that initial biological changes are sufficient to drive many of the changes observed within the joint. The results of this study suggest that Dexamethasone treatment given at the time of drill surgery had a positive impact in reducing the degradation of the cartilage covering the tibial plateau. Interestingly, treatment with this steroid attenuated the mRNA levels for both anabolic and catabolic molecules.

Detection of apoptotic cell death in the thymus of dexamethasone treated rats using [123I]Annexin V and in situ oligonucleotide ligation

In the present study we aimed to establish an animal model of dexamethasone (DEX)-induced apoptosis in the thymus of rats. The degree of apoptosis was determined in the same animals at 6 and 11 h after a single administration of DEX (5 mg/kg, ip) by (a) in vivo biodistribution of the uptake of [(123)I]Annexin V, a biomarker of the early stages of apoptosis; (b) in vitro evaluation of the apoptotic index (percentage of number of apoptotic cells versus total number of cells) in the form of DNA fragmentation, on tissue sections using in situ oligo ligation (ISOL). ISOL demonstrated a 62- and 90-fold increase of apoptotic index at 6 and 11 h after DEX administration respectively, in the outer part of the thymic lobule (cortex) and a 25- and 54-fold increases in the inner part of the thymic lobule (medulla) in the corresponding treatment groups. In the biodistribution study, [(123)I]Annexin V uptake was significantly increased in the thymus of rats 11 h after DEX administration (by 1.3- to 1.4-fold) and significantly decreased at the 6-h time point. We conclude that the specificity of the apoptotic signal provided by isotopic methods in vivo would always require confirmation by complementary in vitro techniques that verify the assessment of ongoing apoptosis accurately.

The effects of repeated corticosteroid administration on the neurogenesis in the neonatal rat

The purpose of this study is to clarify the effects on the brain including neurogenesis pretreated with repeated doses of dexamethasone in the neonatal rat. The 4-day-old Sprague Dawley rats were pretreated with 4 different regimens, namely, single administration of dexamethasone, 2-dose administration, 3-dose administration, and saline administration as a control. Concurrently, bromodeoxyuridine (BrdU), which was incorporated into the dividing cells, was administered. We examined body weight, brain weight, and the number of BrdU-labeled cells in the subventricular zone (SVZ), the subgranular zone (SGZ), and the cortex. Both the body and brain weight of the rats pretreated with dexamethasone were significantly decreased compared with those given saline. Quantitative analysis of BrdU-labeled cells revealed the significant dose-dependent decreases in the SVZ, the SGZ, and the cortex with the dexamethasone treatment. We concluded that the decreases in neurogenesis caused by repeated antenatal corticosteroid therapy might result in the adverse effects on the size of the head at birth.

Up-Regulation of IL-7, Stromal-Derived Factor-1α, Thymus-Expressed Chemokine, and Secondary Lymphoid Tissue Chemokine Gene Expression in the Stromal Cells in Response to Thymocyte Depletion: Implication for Thymus Reconstitution

Three in vivo adult mouse models were established to study which signals are required to restore the postnatal thymus. Single administration of dexamethasone, estradiol, or exposure to sublethal dose of gamma irradiation served as prototype thymus-ablating therapies. In all models, transient thymic atrophy was manifested due to the loss of the predominant portion of CD4- CD8- double negative and CD4+ CD8+ double positive thymocytes and was followed by a complete regeneration of the thymuses. Acute atrophy/regeneration was observed in the dexamethasone and irradiation models; in the estradiol-treated animals, slow kinetics of atrophy and regeneration was observed. Importantly, in both acute and chronic models, high levels of IL-7 mRNA were detected in the thymuses isolated from mice during maximum atrophy. In addition, chemokine gene array analysis of involuted thymuses revealed high levels of mRNA expression of stromal-derived factor-1alpha (SDF-1alpha), thymus-expressed chemokine (TECK), and secondary lymphoid tissue chemokine (SLC) but not of other chemokines. The levels of IL-7, SDF-1alpha, TECK, and SLC mRNA inversely correlated with the kinetics of regeneration. RT-PCR analysis of stromal cells purified from involuted thymuses confirmed increased IL-7, SDF-1alpha, and SLC gene expression in MHC class II+ CD45- epithelial cells and increased IL-7 and TECK gene expression in class II+ CD45+ CD11c+ dendritic cells. Thus, our data showed for the first time that expression of IL-7, SDF-1alpha, TECK, and SLC mRNA is induced in the thymic stroma during T cell depletion and may play an important role in the reconstitution of the adult thymus.

Repeated administration of dexamethasone increases phosphoinositide-specific phospholipase C activity and mRNA and protein expression of the phospholipase C beta 1 isozyme in rat brain.

Altered hypothalamic-pituitary-adrenal (HPA) function has been shown to be associated with changes in mood and behavior. The enzyme phosphoinositide-specific phospholipase C (PI-PLC), an important component of the PI signal transduction system, plays a major role in mediating various physiological functions. In the present study, we investigated the effects of a single dose and of repeated administration (0.5 or 1.0 mg/kg for 10 days) of dexamethasone (DEX), a synthetic glucocorticoid, on PI-PLC activity and on expression of PLC isozymes (beta1, delta1, and gamma1) in rat brain. Repeated administration of DEX (1.0 mg/kg) caused a significant increase in PI-PLC activity and in protein expression of the PLC beta1 isozyme in both membrane and cytosol fractions of cortex and hippocampus; however, the repeated administration of a smaller dose of DEX (0.5 mg/kg) caused these changes only in hippocampus but not in cortex. The increase in PLC beta1 protein was associated with an increase in its mRNA level, as measured by competitive RT-PCR. A single administration of DEX (0.5 or 1.0 mg/kg) to rats had no significant effects on PI-PLC activity or on the protein expression of PLC isozymes. These results suggest that DEX up-regulates PI-PLC in rat brain, which presumably is due to a selective increase in expression of the PLC beta1 isozyme, and that these changes in PI-PLC may be related to HPA axis-mediated changes in mood and behavior.

Administration of dexamethasone up-regulates protein kinase C activity and the expression of gamma and epsilon protein kinase C isozymes in the rat brain.

Altered hypothalamic-pituitary-adrenal (HPA) function (increased plasma cortisol level) has been shown to be associated with mood and behavior. Protein kinase C (PKC), an important component of the phosphatidyl-inositol signal transduction system, plays a major role in mediating various physiological functions. The present study investigates the effects of acute (single) and repeated (10-day) administrations of 0.5 or 1.0 mg/kg doses of dexamethasone (DEX), a synthetic glucocorticoid, on Bmax and KD of [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding, PKC activity, and protein expression of PKC isozymes alpha, beta, gamma, delta, and epsilon in the membrane and the cytosolic fractions of rat cortex and hippocampus. It was observed that repeated administration of 1.0 mg/kg DEX for 10 days caused a significant increase in Bmax of [3H]PDBu binding to PKC, in PKC activity, and in expressed protein levels of the gamma and epsilon isozymes in both the cytosolic and the membrane fractions of the cortex and the hippocampus, whereas a lower dose of DEX (0.5 mg/kg for 10 days) caused these changes only in the hippocampus. On the other hand, a single administration of DEX (0.5 or 1.0 mg/kg) had no significant effect on PKC in the cortex or in the hippocampus. These results suggest that alterations in HPA function from repeated administration of glucocorticoids may modulate PKC-mediated functions.

Treatment with Dexamethasone Alters Yawning Behavior Induced by Cholinergic But Not Dopaminergic Agonist

HIPÓLIDE, D. C., L. L. LOBO, R. DE MEDEIROS, B. NEUMANN, AND S. TUFIK. Treatment with dexamethasone alters yawning behavior induced by cholinergic but not dopaminergic agonist. PHYSIOL BEHAV 65(4/5) 829–832, 1999.—Because stressful manipulations have been reported to modify drug-induced yawning, the present study investigated the effects of single and repeated treatment with a synthetic glucocorticoid, dexamethasone (DEXA) on apomorphine- and pilocarpine-induced yawning in male rats. Neither single nor repeated treatment with DEXA altered apomorphine-induced yawning. Single administration of DEXA, however, resulted in an increased number of yawns induced by pilocarpine. Conversely, repeated administration of DEXA led to a decreased number of yawns induced by pilocarpine. In conclusion, the present findings show that dopaminergic and cholinergic are distinctly altered by DEXA, in terms of yawning behavior when animals received DEXA.

Regulation of renal Na+-K+-ATPase in the rat by adrenal steroids.

The effects of single and multiple injections of aldosterone and dexamethasone on renal Na+-K+-ATPase, in vitro renal gluconeogenesis, and urinary electrolyte excretion were examined in adrenalectomized rats in a dose-dependent manner. Single maximal and supramaximal doses of aldosterone (defined by the effect of electrolyte excretion) had no effect on Na+-K+-ATPase or gluconeogenesis. By contrast, a single administration of dexamethasone (in a dose range that increased fasting blood sugar, stimulated renal gluconeogenesis, and had no mineralocorticoid effects) yielded clear-cut activation of Na+-K+-ATPase. Multiple submaximal doses of dexamethasone produced quantitatively similar stimulation of Na+-K+-ATPase and gluconeogenesis. Multiple supramaximal doses of aldosterone stimulated Na+-K+-ATPase and gluconeogenesis, but maximal and submaximal doses of the hormone were without effect. Aldosterone had no effect on hepatic Na+-K+-ATPase or gluconeogenesis. These results suggest that activation of renal Na+-K+-ATPase can be considered a putative glucocorticoid (not mineralocorticoid) effect. Renal Na+-K+-ATPase activation by chronic aldosterone treatment may be mediated by glucocorticoid receptor sites and, hence, may not represent a genuine mineralocorticoid effect.