Dexamethasone Pretreatment Research Articles

Dexamethasone Pretreatment Alleviates Isoniazid/Lipopolysaccharide Hepatotoxicity: Inhibition of Inflammatory and Oxidative Stress

Isoniazid (INH) remains a cornerstone key constitute of the current tuberculosis management strategy, but its hepatotoxic potentiality remains a significant clinical problem. Our previous findings succeed to establish a rat model of INH hepatotoxicity employing the inflammatory stress theory in which non-injurious doses of inflammatory-mediating agent bacterial lipopolysaccharides (LPS) augmented the toxicity of INH that assist to uncover the mechanisms behind INH hepatotoxicity. Following LPS exposure, several inflammatory cells are activated and it is likely that the consequences of this activation rather than direct hepatocellular effects of LPS underlie the ability of LPS to augment toxic responses. In this study, we investigated the potential protective role of the anti-inflammatory agent dexamethasone (DEX), a potent synthetic glucocorticoid, in INH/LPS hepatotoxic rat model. DEX pre-treatment successfully eliminates the components of the inflammatory stress as shown through analysis of blood biochemistry and liver histopathology. DEX potentiated hepatic anti-oxidant mechanisms while serum and hepatic lipid profiles were reduced. However, DEX administration was not able to revoke the principal effects of cytochrome P450 2E1 (CYP2E1) in INH/LPS-induced liver damage. In conclusion, this study illustrated the DEX-preventive capabilities on INH/LPS-induced hepatotoxicity model through DEX-induced potent anti-inflammatory activity whereas the partial toxicity seen in the model could be attributed to the expression of hepatic CYP2E1. These findings potentiate the clinical applications of DEX co-administration with INH therapy in order to reduce the potential incidences of hepatotoxicity.

Effects of Acute Confinement Stress-induced Hypothalamic-pituitary Adrenal Axis Activation and Concomitant Peripheral and Central Transforming Growth Factor-β1 Measures in Nonhuman Primates

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with anti-inflammatory, immunosuppressive, and neuroprotective properties. The hypothalamic-pituitary-adrenal axis and immune system exert bidirectional influences on each other, via cortisol and TGF-β1, but the exact nature of the interaction is not well characterized. The current study examined the effects, in bonnet macaques (Macaca radiata), of two consecutive acute confinement stress periods in an unfamiliar room while mildly restrained, first without and then with dexamethasone pretreatment (0.01 mg/kg intramuscular). Preceding the confinement studies, a non-stress control condition obtained contemporaneous levels of cortisol and TGF-β1 in both plasma and cerebrospinal fluid to match the confinement stress studies. Subjects were reared under either normative or variable foraging demand conditions. Since there were no rearing effects at baseline or for any of the conditions tested—either for cortisol or TGF-β—the study analyses were conducted on the combined rearing groups. The stress condition increased both plasma and cerebrospinal fluid cortisol levels whereas dexamethasone pretreatment decreased cortisol concentrations to below baseline levels despite stress. The stress condition decreased TGF-β1 concentrations only in cerebrospinal fluid but not in serum. Together, the data suggested that stress-induced reductions of a centrally active neuroprotective cytokine occur in the face of hypothalamic-pituitary-adrenal axis activation, potentially facilitating glucocortoid-induced neurotoxicity. Stress-induced reductions of neuroprotective cytokines prompt exploration of protective measures against glucocorticoid-induced neurotoxicity.

Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance

We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.

The effect of single low-dose dexamethasone on vomiting during awake craniotomy.

Intraoperative vomiting leads to serious respiratory complications that could influence the surgical decision-making process for awake craniotomy. However, the use of antiemetics is still limited in Japan. The aim of this study was to investigate the effect of prophylactically administered single low-dose dexamethasone on the incidence of vomiting during awake craniotomy. The frequency of hyperglycemia was also examined. We conducted a retrospective case review of awake craniotomy for glioma resection between 2012 and 2015. Of the 124 patients, 91 were included in the analysis. Dexamethasone was not used in 43 patients and the 48 remaining patients received an intravenous bolus of 4.95 mg dexamethasone at anesthetic induction. Because of stable operating conditions, no one required conscious sedation throughout functional mapping and tumor resection. Although dexamethasone pretreatment reduced the incidence of intraoperative vomiting (P=0.027), the number of patients who complained of nausea was comparable (P=0.969). No adverse events related to vomiting occurred intraoperatively. Baseline blood glucose concentration did not differ between each group (P=0.143), but the samples withdrawn before emergence (P=0.018), during the awake period (P<0.0001) and at the end of surgery (P<0.0001) showed significantly higher glucose levels in the dexamethasone group. Impaired wound healing was not observed in either group. A single low-dose of dexamethasone prevents intraoperative vomiting for awake craniotomy cases. However, as even a small dose of dexamethasone increases the risk for hyperglycemia, antiemetic prophylaxis with dexamethasone should be administered after careful consideration. Monitoring of perioperative blood glucose concentration is also necessary.

Corticosteroids compromise survival in glioblastoma.

Glioblastoma is the most common and most aggressive primary brain tumour. Standard of care consists of surgical resection followed by radiotherapy and concomitant and maintenance temozolomide (temozolomide/radiotherapy→temozolomide). Corticosteroids are commonly used perioperatively to control cerebral oedema and are frequently continued throughout subsequent treatment, notably radiotherapy, for amelioration of side effects. The effects of corticosteroids such as dexamethasone on cell growth in glioma models and on patient survival have remained controversial. We performed a retrospective analysis of glioblastoma patient cohorts to determine the prognostic role of steroid administration. A disease-relevant mouse model of glioblastoma was used to characterize the effects of dexamethasone on tumour cell proliferation and death, and to identify gene signatures associated with these effects. A murine anti-VEGFA antibody was used in parallel as an alternative for oedema control. We applied the dexamethasone-induced gene signature to The Cancer Genome Atlas glioblastoma dataset to explore the association of dexamethasone exposure with outcome. Mouse experiments were used to validate the effects of dexamethasone on survival in vivo Retrospective clinical analyses identified corticosteroid use during radiotherapy as an independent indicator of shorter survival in three independent patient cohorts. A dexamethasone-associated gene expression signature correlated with shorter survival in The Cancer Genome Atlas patient dataset. In glioma-bearing mice, dexamethasone pretreatment decreased tumour cell proliferation without affecting tumour cell viability, but reduced survival when combined with radiotherapy. Conversely, anti-VEGFA antibody decreased proliferation and increased tumour cell death, but did not affect survival when combined with radiotherapy. Clinical and mouse experimental data suggest that corticosteroids may decrease the effectiveness of treatment and shorten survival in glioblastoma. Dexamethasone-induced anti-proliferative effects may confer protection from radiotherapy- and chemotherapy-induced genotoxic stress. This study highlights the importance of identifying alternative agents such as vascular endothelial growth factor antagonists for managing oedema in glioblastoma patients. Beyond the established adverse effect profile of protracted corticosteroid use, this analysis substantiates the request for prudent and restricted use of corticosteroids in glioblastoma.

Effects of dexamethasone pretreatment on expression of angiopoietin-1, 2 in rats with acute lung injury induced by phosgene

Objective To investigate the effect of dexamethasone on expressions of angiopoietin-1, 2 (Ang-1, 2) in rats with acute lung injury induced by phosgene. Methods A total of 36 SD rats were randomly(random number) divided into 3 groups: normal control group that consisted of the rats with air exposure, phosgene group that consisted of the rats with exposure to 8.33 mg/L phosgene (purity 100%, of the same volume as the inhaled air in the normal control group) for 5 minutes and dexamethasone group that consisted of the rats with caudal vein injection of 2.5 mg/kg dexamethasone an hour before exposure to the same dose of phosgene. Wet and dry ratio of the lung (W/D) was calculated, and leukocyte count and total protein content of bronchoalveolar lavage fluid (BALF) were recorded 2 hours later. The concentrations of Ang-1, 2 in the serum and BALF were measured by enzyme-linked immunosorbent assay (ELISA). Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the mRNA levels of Ang-1, 2 and Tie-2 in the lung tissue. The protein expression of Ang-1, 2 and Tie-2 in the lung tissue were quantified by Western blot. Results Compared with phosgene group, the lung W/D, protein content of BALF and WBC count in dexamethasone group were significantly decreased(P<0.01). Compared with normal control group, Ang-1 and Tie-2 expressions in phosgene group were significantly decreased (P<0.01). Compared with phosgene group, the serum, BALF and lung tissue of Ang-1 and Tie-2 expressions in dexamethasone group was significantly increased(P<0.01). Compared with normal control group, the serum, BALF and lung tissue of Ang-2 expressions in phosgene group were significantly increased (P<0.01). Compared with phosgene group, the serum, BALF and lung tissue of Ang-2 expressions in dexamethasone group were significantly decreased(P<0.05, P<0.01). Conclusion Dexamethasone has a beneficial effect on acute lung injury induced by phosgene in rats by inhibition of Ang-2 and increase in Ang-1 and Tie-2 expressions. Key words: Dexamethasone; Phosgene; Acute Lung Injury; Angiopoietin-1 (Ang-1); Angiopoietin-2 (Ang-2)

Anti-inflammatory effect of lycopene on endotoxin-induced uveitis in rats.

We evaluated the efficacy of lycopene, a dietary carotenoid and potent antioxidant, against ocular inflammation and oxidative stress in an experimental uveitis model. Endotoxin-induced uveitis (EIU) was induced in Sprague-Dawley rats by a single subcutaneous injection of 200 μg lipopolysaccharide (LPS). Induction of EIU was preceded by daily intraperitoneal injection of 10 mg/kg lycopene for three consecutive days (Lycopene + LPS group) or equivolume vehicle (Vehicle + LPS group). A positive control group received 1 mg/kg dexamethasone pretreatment (DEX + LPS), and a negative control group received daily vehicle injection but no LPS (Vehicle Control). Twenty-four hours after LPS or final vehicle administration, eyes were enucleated, and aqueous humor was collected for measurement of the number of infiltrating cells, total protein concentration, and levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and oxidative stress markers. Inflammatory response severity was compared among groups clinically and histopathologically. Infiltrating cell number, total protein concentration, and NO, TNF-α, and IL-6 levels were significantly elevated in the aqueous humor of Vehicle + LPS group rats compared to Vehicle Controls. Compared to the Vehicle + LPS group, lycopene pretreatment significantly reduced aqueous humor concentrations of oxidative stress markers, NO (0.29 ± 0.1 μM vs. 0.19 ± 0.1 μM, p=0.003), TNF-α (71.0 ± 22.3 ng/ml vs. 50.1 ± 2.1 ng/ml, p=0.043), and IL-6 (121.6 ± 3.0 pg/ml vs. 111.1 ± 5.6 pg/ml, p=0.008). Inflammatory score was also reduced (2.0 ± 0.0 vs. 0.4 ± 0.5, p=0.001). Lycopene reduced the infiltrating cell count and protein concentration, but differences did not reach significance. Most lycopene effects were equivalent to dexamethasone. Lycopene may aid in the clinical management of uveitis by suppressing inflammation and oxidative stress.

The effects of proinflammatory cytokines on the apoptosis of corneal endothelial cells following argon laser iridotomy

The aim of this study was to evaluate the relationship between the expression of proinflammatory cytokines and the apoptosis of corneal endothelial cells after argon laser iridotomy (ALI). ALI was performed on each quadrant of the iris in the right eye of mice (ALI1 group). Left eyes were used as control group. The levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and interferon (IFN)-γ in mice eyes were measured, and TUNEL staining was performed 12 h after ALI. Mice in the ALI-Dexa group were pretreated daily with an intraperitoneal injection of dexamethasone for 4 days before undergoing ALI and compared with mice without dexamethasone pretreatment (ALI2 group). Twelve corneas from six rabbits were incubated ex vivo with (n = 6) or without (n = 6) IL-1β. TUNEL staining was performed 24 h after ex vivo incubation. In the mice experiment, the levels of IL-1β, TNF-α, TGF-β, and IFN-γ were increased in the ALI1 group compared to the control group. Although many TUNEL-positive cells were observed in the ALI1 group, those were not detected in the control group. Dexamethasone pretreatment inhibited the increase in the levels of all four proinflammatory cytokines and reduced TUNEL-positive cells. In the rabbit experiment, TUNEL-positive cells were increased in the incubated corneas with IL-1β compared to those without IL-1β. Expression of proinflammatory cytokines following ALI seems to play a role in the apoptosis of corneal endothelial cells after ALI. Dexamethasone pretreatment inhibited increases in proinflammatory cytokines and reduced the apoptosis of corneal endothelial cells.

Effects of Candida albicans on the expression of tumor necrosis factor-α and activation of the intracellular signaling molecule p38MAPK in a human acute monocytic leukemia cell line THP-1

Objective To investigate the effects of Candida albicans on the expression of tumor necrosis factor-α (TNF-α) and activation of the intracellular signaling molecule p38 mitogen-activated protein kinase (p38MAPK) in a human acute monocytic leukemia cell line THP-1. Methods Some THP-1 cells were divided into several groups in vitro: two C. albicans groups treated with 105 CFU/ml and 106 CFU/ml heat-killed C. albicans respectively, a lipopolysaccharide (LPS) group treated with 100 μg/L LPS, a blank control group treated with RPMI 1640 medium, two dexamethasone-inhibited groups pretreated with 40 μg/L dexamethasone for 30 minutes followed by treatment with 106 CFU/ml heat-killed C. albicans and LPS respectively. After treatment for 1, 3 and 6 hours, real-time fluorescence-based quantitative PCR was performed to measure TNF-α mRNA expression in THP-1 cells in the above groups. Enzyme-linked immunosorbent assay (ELISA) was conducted to determine the level of TNF-α protein in the supernatant of THP-1 cells treated with 106 CFU/ml heat-killed C. albicans, 100 μg/L LPS or RPMI 1640 medium (blank control group) for 24 hours. Western blot was performed to measure the protein expression of p38MAPK and phosphorylated p38MAPK in THP-1 cells after treatment with 106 CFU/ml heat-killed C. albicans or RPMI 1640 medium (blank control group) for 30 and 60 minutes. Statistical analysis was carried out by using two-way analysis of variance, one-way analysis of variance and the least significant difference (LSD)-t test. Results Significant differences were observed in the mRNA expression level of TNF-α among the C. albicans groups, LPS group and blank control group (F=110.98, P< 0.001). The mRNA expression level of TNF-α in THP-1 cells increased over time in a time-dependent manner after C. albicans treatment, with significant differences among different time points (F=701.680, P< 0.001). Compared with the blank control group, both 106-CFU/ml C. albicans group and LPS group showed a significant increase in TNF-α protein expression (6385.70±533.99 ng/L and 3212.06±353.00 ng/L vs. 147.10±0.53 ng/L, P< 0.001 and 0.005, respectively). An obvious increase was observed in the expression level of phosphorylated p38MAPK protein, but no significant changes were noted in that of p38MAPK protein, in THP-1 cells treated with 106 CFU/ml C. albicans for 30 and 60 minutes compared with the blank control group. The mRNA expression level of TNF-α significantly decreased in dexamethasone-pretreated 106-CFU/ml C. albicans group and LPS group compared with those without dexamethasone pretreatment (3.77±0.62 vs. 208.50±10.50, 6.20±1.93 vs. 161.35±1.65, both P< 0.001). Conclusions Heat-killed C. albicans can induce the activation of p38MAPK in and secretion of TNF-α by human THP-1 cells, which then participate in the innate immune response against C. albicans. Key words: Candida albicans; Leukemia, monocytic, acute; Tumor necrosis factor-alpha; p38 Mitogen-activated protein kinases; Cell line, tumor

Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro.

Platycodin D (PLD) is the major triterpene saponin in the root of Platycodon grandiflorum (Jacq.) with various pharmacological activities. The purpose of the present study was to evaluate the protective effects and possible mechanisms of PLD on acute lung injury (ALI) both in vivo and in vitro. In vivo, we used two ALI models, lipopolysaccharide (LPS)-induced ALI and bleomycin (BLE)-induced ALI to evaluate the protective effects and possible mechanisms of PLD. Female BALB/c mice were randomly divided into the following groups: control group, LPS group, LPS plus pre-treatment with dexamethasone (2 mg/kg) group, LPS plus pre-treatment with PLD groups (50 mg/kg, 100 mg/kg), LPS plus post-treatment with dexamethasone (2 mg/kg) group, LPS plus post-treatment with PLD groups (50 mg/kg, 100 mg/kg), BLE group, BLE plus pre-treatment with dexamethasone (2 mg/kg) group, BLE plus pre-treatment with PLD groups (50 mg/kg, 100 mg/kg), BLE plus post-treatment with dexamethasone (2 mg/kg) group, and BLE plus post-treatment with PLD groups (50 mg/kg, 100 mg/kg). PLD was orally administered before or after LPS or BLE challenge with mice. Mice were sacrificed, and lung tissues and bronchoalveolar fluid (BALF) were prepared for further analysis. Our results showed that PLD significantly decreased lung wet-to-dry weight ratio (lung W/D weight ratio), total leukocyte number and neutrophil percentage in the BALF, and myeloperoxidase (MPO) activity of lung in a dose-dependent manner. Besides, cytokine levels, including interleukin (IL)-6, tumor neurosis factor (TNF)-α were also found significantly inhibited in BALF. Furthermore, PLD effectively inhibited the expressions of nuclear factor κB (NF-κB), Caspase-3 and Bax in the lung tissues, as well as restored the expression of Bcl-2 in the lungs and improved the superoxide dismutase (SOD) activity in BALF. In vitro, we used LPS-challenged cell model to evaluate the protective effects and possible mechanisms of PLD. MLE-12 cells were stimulated with LPS in the presence and absence of PLD. The levels of TNF-α, IL-6 and the expressions of NF-κB, Caspase-3, and Bax were remarkably down-regulated, while the expression of bcl-2 was significantly up-regulated in PLD treatment groups in MLE-12 cells. These results showed that the administration of PLD improved ALI both in vivo and in vitro, possibly through suppressing apoptosis and inflammation.

Dexamethasone suppresses of IL-33-mediated mast cell activation in vitro and in vivo (HYP4P.314)

Abstract Dexamethasone, a synthetic member of the glucocorticoid class of steroid drugs is known for its immunosuppressant and anti-inflammatory effects. Mast cells, critical effectors of allergic disease, can be activated by IL-33, a pro-inflammatory member of the IL-1 family. We found that Dexamethasone potently suppresses IL-33-stimulated cytokine secretion by mouse mast cells. We similarly found that Dexamethasone treatment in vivo reduced IL-33-mediated cytokine production and neutrophil infiltration in the murine peritoneum. We compared the activation status of signaling proteins during IL-33 stimulation, and found that Dexamethasone pretreatment significantly reduced Erk phosphorylation. However, we also observed that Dexamethasone-mediated suppression occurred when it was added simultaneously with IL-33, suggesting that inhibition occurrs even prior to Erk blockade. The effect of Dexamethasone on IL-33 stimulated NFkB-mediated gene transcription is currently under investigation. Our data show that Dexamethasone, a well-established therapy for inflammatory disease, can suppress IL-33-mediated mast cell activation, and may therefore be effective for treating diseases now being attributed to IL-33 effects.

The Cardioprotective Effect of Dexamethasone through Activation of RISK Pathway

BackgroundTreatment of ischemic heart disease, mainly focuses on returning blood flow back to the ischemic area. However, irreversible cell damage caused by reperfusion is the main risk of these approaches. The reperfusion injury salvage kinase (RISK) pathway can be targeted to decrease cell death and restore cell function during ischemia/reperfusion (I/R). Glucocorticoids are part of the feedback mechanism in the immune system that inhibits inflammation. Their intracellular effect is mediated by binding to the glucocorticoid receptor (GR). Dexamethasone(DEX) is a corticosteroid medicine used for anti‐inflammation which has a higher affinity to the GR than cortisol.MethodsThe effects of DEX was studied in an acute I/R injury model in which the left anterior descending coronary artery was occluded. Ex vivo mouse heart perfusion Langendorff system was used to measure the effects on glucose receptor 4 (GLUT4) translocation.Results‐Significant recovery of cardiac function was observed following DEX pretreatment during I/R injury. DEX activated the protective RISK pathways (includes ERK, AKT, and AMPK) significantly in a time and dose dependent manner. Furthermore, AMPK's translocation into nucleus was found after DEX treatment compared with I/R only. To deeply investigate the reason of AMPK translocation, immunoprecipitation was conducted. Results showed GR could interact with AMPK and recruit Sestrin 2‐LKB1 complex during I/R, which helped AMPK's phosphorylation and translocation during I/R. Moreover, one of AMPK's downstream effects ‐ stimulating GLUT4′s translocation to cell surface ‐ was also triggered after DEX stimulation.ConclusionDEX's cardioprotective function is achieved by activating the RISK protective signaling pathways during I/R.

Additive Suppression of LPS-Induced IL-10 and TNF-α by Pre-treatment of Dexamethasone and SB203580 in a Murine Alveolar Macrophage Cell Line (MH-S).

P38 inhibitors are potent anti-inflammatory agents with distinctive mechanism of action from corticosteroid; the potential combined use of both anti-inflammatory agents could be an effective treatment for inflammatory lung disease; however, the impact of such combination on the homeostasis of immune response was poorly understood. To investigate the combined effect of dexamethasone (DEX) and/or SB203580 on tumor necrosis factor (TNF)-α (pro-inflammatory) and interleukin (IL)-10 (anti-inflammatory) secretion in mouse alveolar macrophage cell line. Secreted TNF-α and IL-10 were measured by ELISA. Phosphorylated STAT3 were investigated using Western blotting and immunocytochemistry. Pre-treatment of DEX or SB203580 inhibited lipopolysaccharide (LPS)-stimulated IL-10, TNF-α secretion, and STAT3 phosphorylation. Combined use of both agents showed stronger inhibitory effect. Combining DEX and SB203580 showed strong inhibition on the LPS-induced IL-10 secretion and STAT3 phosphorylation, which might reflect a very important drawback from the combined use of both anti-inflammatory agents.

Dexamethasone protects neonatal hypoxic-ischemic brain injury via L-PGDS-dependent PGD2-DP1-pERK signaling pathway.

Background and PurposeGlucocorticoids pretreatment confers protection against neonatal hypoxic-ischemic (HI) brain injury. However, the molecular mechanism remains poorly elucidated. We tested the hypothesis that glucocorticoids protect against HI brain injury in neonatal rat by stimulation of lipocalin-type prostaglandin D synthase (L-PGDS)-induced prostaglandin D2 (PGD2)-DP1-pERK mediated signaling pathway.MethodsDexamethasone and inhibitors were administered via intracerebroventricular (i.c.v) injections into 10-day-old rat brains. Levels of L-PGD2, D prostanoid (DP1) receptor, pERK1/2 and PGD2 were determined by Western immunoblotting and ELISA, respectively. Brain injury was evaluated 48 hours after conduction of HI in 10-day-old rat pups.ResultsDexamethasone pretreatment significantly upregulated L-PGDS expression and the biosynthesis of PGD2. Dexamethasone also selectively increased isoform pERK-44 level in the neonatal rat brains. Inhibitors of L-PGDS (SeCl4), DP1 (MK-0524) and MAPK (PD98059) abrogated dexamethasone-induced increases in pERK-44 level, respectively. Of importance, these inhibitors also blocked dexamethasone-mediated neuroprotective effects against HI brain injury in neonatal rat brains.ConclusionInteraction of glucocorticoids-GR signaling and L-PGDS-PGD2-DP1-pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury.

Loss of the Endothelial Glucocorticoid Receptor Prevents the Therapeutic Protection Afforded by Dexamethasone after LPS

Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.

A clinical study of pretreatment with different doses of dexamethasone in the prevention of docetaxel-induced hypersensitivity.

e13514 Background: To evaluate the efficacy and safety of dexamethasone pretreatment regimen with different doses in the prevention of docetaxel-induced hypersensitivity reaction (HSR). Methods: On...

Dexamethasone suppresses IL-33-mediated mast cell activation (HYP3P.409)

Abstract Dexamethasone, a potent synthetic member of the glucocorticoid class of steroid drugs is known for its immunosuppressant and anti-inflammatory effects. The present research investigates the role of this anti-allergic drug in suppressing IL-33-mediated mast cell activation. IL-33 is a novel cytokine of IL-1 family, which promotes mast cells to produce inflammatory cytokines independently of IgE-FcεRI signals. Initial studies have shown that micromolar quantities of dexamethasone suppress the production of TNF-α and IL-6 by IL-33-stimulated mast cells. While confirming these results by intracellular staining, it was observed that dexamethasone not only decreases the fraction of cytokine-positive cells but also causes a drop in cytokine production per cell. Although dexamethasone pretreatment resulted in a significant reduction in the IL-33 receptor subunit T1/ST2, this did not correlate with decreased cytokine production. These results demonstrate the ability of dexamethasone to suppress mast cell activation during innate immune responses, and support further work into the mechanisms by which this occurs.

Effects of promethazine or dexamethasone pretreatment on histamine release induced by mivacurium in pediatric patients

Objective To evaluate the effects of promethazine or dexamethasone pretreatment on histamine release induced by mivacurium in pediatric patients.Methods Eighty pediatric patients,of ASA physical status Ⅰ or Ⅱ,aged 4-10 yr,weighing 14-30 kg,scheduled for elective tonsillectomy and adenoidectomy,were randomized into 4 groups (n =20 each) using a random number table:rocuronium group (group R),mivacurium group (group M),dexamethasone + mivacurium group (group DM) and promethazine + mivacurium group (group PM).Dexamethasone 0.2 mg/kg and promethazine 0.5 mg/kg were injected intramuscularly at 60 min before anesthesia in DM and PM groups,respectively.Anesthesia was induced with midazolam,propofol,fentanyl and rocuronium 600 μg/kg (in group R) or mivacurium 200 μg/kg (in M,MD and MP groups).At 1 min before administration of muscle relaxants and 1,3 and 5 min after administration of muscle relaxants,MAP and HR were recorded,blood samples were taken from the radial artery for determination of plasma histamine concentrations,and the cutaneous adverse reactions were observed.Results Compared with group R,MAP was significantly decreased at T1-3,HR and plasma histamine concentrations were increased at Ti,2,and the grade of cutaneous adverse reactions was increased in group M,MAP was decreased at T1,2,HR was increased at T1-3,plasma histamine concentrations were increased at T1 in group DM,and plasma histamine concentrations were increased at T1 in group PM.Compared with group M,MAP was significantly increased at T2 in group DM,MAP was increased and HR was decreased at T1-3,plasma histamine concentrations were decreased at T1,2 in group PM,and the grade of cutaneous adverse reactions was decreased in DM and PM groups.Conclusion Promethazine pretreatment can decrease the mivacurium-caused release of histamine in pediatric patients,while dexamethasone pretreatment has no such effects. Key words: Dexamethasone ; Promethazine ; Ischemic preconditioning; Androstanols ; Histamine ; Child

Effect of Dexamethasone Administered With Magnesium Sulfate on Inflammation-Mediated Degradation of the Blood—Brain Barrier Using an In Vitro Model

Patients at risk for preterm delivery are frequently administered both antenatal steroids for fetal maturation and magnesium sulfate for neuroprotection. In this study, we investigate whether steroids coadministered with magnesium sulfate preserve blood-brain barrier integrity in neuroinflammation. Human umbilical vein endothelial cells were grown in astroglial conditioned media in a 2-chamber cell culture apparatus. Treatment with tumor necrosis factor-α (TNF-α) or catalytically active recombinant matrix metalloproteinase 9 (MMP-9) simulated neuroinflammation. Membrane integrity was assessed by zona occludens 1 (ZO-1) immunoreactivity, permeability to fluorescently conjugated dextran, and transendothelial electrical resistance (TEER). The TNF-α and MMP-9 treatment increased the rate of dextran transit, decreased TEER, and decreased ZO-1 immunoreactivity at junctional interfaces. Dexamethasone pretreatment alone or in combination with 0.5 mmol/L magnesium sulfate preserved monolayer integrity after inflammatory insult. Magnesium sulfate alone was not protective. This study supports a possible interaction between steroids and magnesium in neuroprotection.

Inhibition of Nerve Growth Factor-Induced Neurite Outgrowth from PC12 Cells by Dexamethasone: Signaling Pathways through the Glucocorticoid Receptor and Phosphorylated Akt and ERK1/2

Glucocorticoids are important mediators of the stress response and are commonly employed as drugs for the suppression of immune rejection after organ transplantation. Previous investigations uncovered the possibility of mood depression in patients undergoing long-term treatment with synthetic glucocorticoids, including dexamethasone (DEX). Exogenous glucocorticoids and their synthetic derivatives can also adversely affect the development of the central nervous system. Although neurite extension from rat pheochromocytoma-derived PC12 cells and a variety of primary neurons is stimulated by nerve growth factor (NGF), and signaling pathways triggered by the binding of NGF to tyrosine kinase receptor type 1 (TrkA) function in both neurite outgrowth and neuronal survival, the effect of DEX on the activation of regulatory proteins and pathways downstream of TrkA has not been well characterized. To analyze the influence of DEX on NGF-induced neurite outgrowth and signaling, PC12 cells, a widely utilized model of neuronal differentiation, were pretreated with the glucocorticoid prior to NGF induction. NGF-induced neurite outgrowth was attenuated by pretreatment with DEX, even in the absence of DEX after the addition of NGF. Moreover, DEX suppressed the phosphorylation of Akt and extracellular-regulated kinase 1/2 (ERK1/2) in the neurite outgrowth signaling cascade initiated by NGF. Finally, the glucocorticoid receptor (GR) antagonist, RU38486, counteracted the inhibitory effect of DEX pretreatment, not only on the phosphorylation of Akt and ERK1/2, but also on neurite extension from PC12 cells. These results suggest that DEX binding to the GR impairs NGF-promoted neurite outgrowth by interfering with the activation/phosphorylation of Akt and ERK1/2. These novel findings are likely to be useful for elucidating the central nervous system depressive mechanism(s) of action of DEX and other glucocorticoids.