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Synthetic Glucocorticoids (synthetic + glucocorticoid)

Distribution by Scientific Domains

Medical Sciences	40%
Life Sciences	40%

Selected Abstracts

Methylprednisolone inhibits the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans in reactivated astrocytes

GLIA, Issue 13 2008
Wei-Lin Liu
Abstract Reactive gliosis caused by post-traumatic injury often results in marked expression of chondroitin sulfate proteoglycan (CSPG), which inhibits neurite outgrowth and regeneration. Methylprednisolone (MP), a synthetic glucocorticoid, has been shown to have neuroprotective and anti-inflammatory effects for the treatment of acute spinal cord injury (SCI). However, the effect of MP on CSPG expression in reactive glial cells remains unclear. In our study, we induced astrocyte reactivation using ,-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and cyclothiazide to mimic the excitotoxic stimuli of SCI. The expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivation, and CSPG neurocan and phosphacan were significantly elevated by AMPA treatment. The conditioned media from AMPA-treated astrocytes strongly inhibited neurite outgrowth of rat dorsal root ganglion neurons, and this effect was reversed by pretreatment with MP. Furthermore, MP downregulated GFAP and CSPG expression in adult rats with SCI. Additionally, both the glucocorticoid receptor (GR) antagonist RU486 and GR siRNA reversed the inhibitory effects of MP on GFAP and neurocan expression. Taken together, these results suggest that MP may improve neuronal repair and promote neurite outgrowth after excitotoxic insult via GR-mediated downregulation of astrocyte reactivation and inhibition of CSPG expression. © 2008 Wiley-Liss, Inc. [source]

Sex differences in response to steroids in preterm sheep lungs are not explained by glucocorticoid receptor number or binding affinity,

PEDIATRIC PULMONOLOGY, Issue 1 2001
Jana Kovar BScHons
Abstract We recently reported that prenatal glucocorticoid therapy is less effective at promoting an improvement in lung function in male than in female sheep. This observation, and the higher incidence of respiratory distress syndrome in human males, suggests that the male fetal lung may be less responsive to glucocorticoids than is the female fetal lung. Since glucocorticoids are known to exert their effects via specific cytoplasmic glucocorticoid receptors (GR), we hypothesized that there may be sexual dimorphism in either the number or binding affinity of lung GR. To test the hypothesis, binding of dexamethasone (a synthetic glucocorticoid, 0.5,40 nM) by cytosolic fractions of male (n,=,16) and female (n,=,16) fetal sheep lung was measured at 125 days gestation (term,=,148 days). Scatchard analysis of dexamethasone binding showed that the total number of GR (Bmax) did not significantly differ between male (346,±,42 fmol/mg protein) and female (277,±,23 fmol/mg protein) fetuses. The measured binding affinity (Kd) in male fetal lungs (6.85,±,0.43 nM) was not significantly different from that in females (8.46,±,1.02 nM). In conclusion, this study suggests that sex differences in fetal sheep lung responses to glucocorticoid therapy are not due to differences in the number or binding affinity of lung GR. Pediatr Pulmonol. 2001; 32:8,13. © 2001 Wiley-Liss, Inc. [source]

Two CCAAT/enhancer binding protein sites in the cytochrome P4503A1 locus

FEBS JOURNAL, Issue 3 2003
Potencial role in the glucocorticoid response
Induction of CYP3A genes by the ligand-activated pregnane-X-receptor (PXR) involves the interaction of other as yet unidentified liver transcription factors. Here we show that the CYP3A1 promoter contains two active sites controlled by the CCAAT/enhancer-binding protein , (C/EBP,), previously shown to regulate a number of liver stress response genes. We have identified two functional C/EBP binding sites at the CYP3A1 promoter that confer luciferase activity to C/EBP, cotransfected CHO cells. When inserted upstream of a thymidine kinase promoter, oligonucleotides corresponding to these elements (,350/,311 and ,628/,608), increase reporter gene expression when cotransfected with a C/EBP, expression vector. Point mutations in the most conserved nucleotides in either element prevent binding of C/EBP, and abolish transactivation of the CYP3A1 promoter. Moreover, we demonstrate that C/EBP, accumulates in the rat liver nuclei in response to dexamethasone, and that under these conditions C/EBP, binds to the CYP3A1 promoter elements. Our results suggest a correlation between transcription of C/EBP,, nuclear protein function and induction of CYP3A1 by dexamethasone in the liver. They also support the notion that C/EBP, participates in the up-regulation of the CYP3A1 gene in response to synthetic glucocorticoids. [source]

Central nervous system effects of natural and synthetic glucocorticoids

PSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 5 2009
Pierluigi Fietta MD
Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5,10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC. [source]

Prenatal synthetic glucocorticoid exposure alters hypothalamic,pituitary,adrenal regulation and pregnancy outcomes in mature female guinea pigs

THE JOURNAL OF PHYSIOLOGY, Issue 5 2010
Elizabeth Dunn
Preterm delivery occurs in approximately 10% of all pregnancies. Prenatal exposure to synthetic glucocorticoids (sGCs) reduces the incidence of respiratory distress syndrome (RDS) in these babies. Therefore, administration of multiple courses of sGCs became common practice. Animal and human studies have demonstrated that multiple courses of sGCs can have long-term effects. While the majority of animal studies have been undertaken in male offspring, it is emerging that there are profound sex differences in the consequences of prenatal sGC exposure. To our knowledge, no studies have determined the effects of prenatal sGC exposure on hypothalamic,pituitary,adrenal (HPA) axis function in female offspring while accounting for reproductive cycle status, or determined if there are effects on pregnancy parameters. Pregnant guinea pigs were administered three courses of betamethasone (Beta), dexamethasone (Dex) or vehicle on gestational days 40/41, 50/51 and 60/61. In adulthood (age range: postnatal days 126,165), basal and activated HPA axis function were assessed at various stages of the reproductive cycle. The female offspring were then mated and underwent an undisturbed pregnancy. Females were killed in the luteal phase of the reproductive cycle following litter weaning, and molecular analysis undertaken. In the luteal phase, Beta-exposed females exhibited significantly lower basal salivary cortisol levels (P < 0.05). Dex-exposed females also exhibited significantly lower basal salivary cortisol levels during the luteal phase (P < 0.05), but increased basal salivary cortisol levels during the ostrous phase (P < 0.01). The Beta-exposed females exhibited increased glucocorticoid receptor (GR) mRNA expression in the CA1/2 region of the hippocampus (P < 0.05) and MC2R mRNA in the adrenal cortex (P < 0.05). The Dex-exposed animals exhibited higher hippocampal GR and mineralocorticoid receptor (MR) mRNA levels (P < 0.05). Beta-exposed females showed reduced fecundity (P < 0.05). In Dex-exposed females there was a lower male to female sex ratio. In conclusion, prenatal sGC exposure affects HPA axis activity, in a cycle-dependent manner, and long-term reproductive success. The clinical implications of the findings on endocrine function and pregnancy in females are profound and further follow-up is warranted in human cohorts. Furthermore, we have shown there are considerable difference in phenotypes between the Beta- and Dex-exposed females and the specific endocrine and maternal outcome is contingent on the specific sGCs administered during pregnancy. [source]