Effects Of Glucocorticoids Research Articles

Accumulation of Fat Not Responsible for Femoral Head Necrosis, Revealed by Single-Cell RNA Sequencing: A Preliminary Study.

The etiology of osteonecrosis of the femoral head (ONFH) is not yet fully understood. However, ONFH is a common disease with high morbidity, and approximately one-third of cases are caused by glucocorticoids. We performed single-cell RNA sequencing of bone marrow to explore the effect of glucocorticoid on ONFH. Bone marrow samples of the proximal femur were extracted from four participants during total hip arthroplasty, including two participants diagnosed with ONFH for systemic lupus erythematosus (SLE) treated with glucocorticoids (the case group) and two participants with femoral neck fracture (the control group). Unbiased transcriptome-wide single-cell RNA sequencing analysis and computational analyses were performed. Seventeen molecularly defined cell types were identified in the studied samples, including significantly dysregulated neutrophils and B cells in the case group. Additionally, fatty acid synthesis and aerobic oxidation were repressed, while fatty acid beta-oxidation was enhanced. Our results also preliminarily clarified the roles of the inflammatory response, substance metabolism, vascular injury, angiogenesis, cell proliferation, apoptosis, and dysregulated coagulation and fibrinolysis in glucocorticoid-induced ONFH. Notably, we list the pathways that were markedly altered in glucocorticoid-induced ONFH with SLE compared with femoral head fracture, as well as their common genes, which are potential early therapeutic targets. Our results provide new insights into the mechanism of glucocorticoid-induced ONFH and present potential clues for effective and functional manipulation of human glucocorticoid-induced ONFH, which could improve patient outcomes.

Effects of different doses of glucocorticoids on postoperative atrial fibrillation: a meta-analysis

BackgroundPostoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery, and its occurrence is closely related to inflammation. This paper intends to apply meta-analysis to investigate the effect of glucocorticoids on POAF.MethodsPubMed, Embase, Web of Science, and Cochrane Library were searched using the internationally recognized systematic evaluation and retrieval strategy. Two review authors independently selected relevant studies and extracted data based on the Cochrane handbook for systematic reviews of interventions approach. Stata 17 was used for data analysis. In the subgroup analysis, we grouped the participant data according to differences in glucocorticoids dose and type of surgery. At the same time, we also conducted a meta-analysis on the possible infection and gastrointestinal injury caused by glucocorticoids use.Results27 studies and 14,442 patients were finally included. Results from the random-effects model indicated that the incidence of POAF was lower in glucocorticoid group (RR 0.80, 95% CI 0.71–0.92, P = 0.001). According to the subgroup analysis result, low doses of glucocorticoids reduced the incidence of POAF (RR 0.81, 95% CI 0.71–0.92, P = 0.001). The effect of high doses glucocorticoids on the POAF was not statistically significant (RR 0.81, 95% CI 0.56–1.19, P = 0.286). In the coronary artery bypass grafting (CABG) subgroup, the glucocorticoids reduced the incidence of POAF (RR 0.71, 95% CI 0.58–0.87, P = 0.001). In the CABG OR Valvular Surgery group, the effect of glucocorticoids on POAF was not statistically significant (RR 0.88, 95% CI 0.75–1.03, P = 0.108). 15 studies documented postoperative complications of infection, two studies were excluded from the system because the end point event was 0, and meta-analysis showed no increased risk of infection from glucocorticoid use (RR 0.85, 95% CI 0.68–1.06, P = 0.158). Eight studies documented the effects of glucocorticoids on gastrointestinal diseases, and meta-analysis showed no differences between the two groups (RR 1.12, 95% CI 0.83–1.50, P = 0.450).ConclusionThe use of glucocorticoids can reduce the incidence of POAF. The subgroup analysis result showed that low-dose glucocorticoids were more effective than high-dose glucocorticoids in inhibiting POAF. The use of glucocorticoids in CABG alone can better inhibit the occurrence of POAF. The effects of glucocorticoids on infection and gastrointestinal injury were not statistically significant.Review registration: PROSPERO, CRD42022304521.

Glucocorticoids for croup in children.

Glucocorticoids for croup in children.

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity.

Metabolic syndrome is considered the precursor of type 2 diabetes mellitus. Tuberculosis is a leading infection that constitutes a global threat remaining a major cause of morbi-mortality in developing countries. People with type 2 diabetes mellitus are more likely to suffer from infection with Mycobacterium tuberculosis. For both type 2 diabetes mellitus and tuberculosis, there is pulmonary production of anti-inflammatory glucocorticoids mediated by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal hormone dehydroepiandrosterone (DHEA) counteracts the glucocorticoid effects of cytokine production due to the inhibition of 11β-HSD1. Late advanced tuberculosis has been associated with the suppression of the Th1 response, evidenced by a high ratio of cortisol/DHEA. In a murine model of metabolic syndrome, we determined whether DHEA treatment modifies the pro-inflammatory cytokines due to the inhibition of the 11β-HSD1 expression. Since macrophages express 11β-HSD1, our second goal was incubating them with DHEA and Mycobacterium tuberculosis to show that the microbicide effect was increased by DHEA. Enoyl-acyl carrier protein reductase (InhA) is an essential enzyme of Mycobacterium tuberculosis involved in the mycolic acid synthesis. Because 11β-HSD1 and InhA are members of a short-chain dehydrogenase/reductase family of enzymes, we hypothesize that DHEA could be an antagonist of InhA. Our results demonstrate that DHEA has a direct microbicide effect against Mycobacterium tuberculosis; this effect was supported by in silico docking analysis and the molecular dynamic simulation studies between DHEA and InhA. Thus, DHEA increases the production of pro-inflammatory cytokines in the lung, inactivates GC by 11β-HSD1, and inhibits mycobacterial InhA. The multiple functions of DHEA suggest that this hormone or its synthetic analogs could be an efficient co-adjuvant for tuberculosis treatment.

Rare localization of avascular necrosis during treatment of COVID-19 with glucocorticosteroids

The development of bony avascular necrosis induced by glucocorticoid treatment of COVID-19 is a common adverse effect, with femoral head being the most commonly affected. Timely detection of avascular necrosis is important in the prevention of osteoarthrosis and other complications.
 We present a clinical case of a 54-year-old patient hospitalized for novel coronavirus infection with complaints of severe pain in both knees 2 weeks after the disease onset. Magnetic resonance imaging revealed pronounced changes in both knees, corresponding to avascular necrosis. The results of conservative therapy, including non-steroidal anti-inflammatory drugs and bisphosphonate bone resorption inhibitors, produced a pronounced positive result. At follow-up examination 3 months later, there was no pain, but the knee joints still had slight restrictions of movement. Magnetic resonance imaging showed a significant decrease in the previously detected changes.
 The side effects of glucocorticoids (impaired glucose tolerance, increased blood pressure, tachycardia, gastrointestinal erosive ulcers, sleep disorders, etc.) are widely known, but knee osteonecrosis caused by steroid intake rarely comes to the attention of clinicians. This clinical case emphasizes the complex nature of osteonecrosis pathogenesis and demonstrates a wide range of complications in corticosteroid therapy.

Evaluation of the effect of glucocorticoid treatment on adrenocortical functions by monitoring endogenous hydrocortisone in horses.

Glucocorticoid preparations have anti-inflammatory effects, and are commonly used in the equine clinical setting; however, such treatments can cause a number of side effects. Adrenal insufficiency is an adverse effect induced by the suppression of adrenal function following drug administration. This study aimed to investigate the influence of two glucocorticoid preparations, dexamethasone and hydrocortisone, on adrenocortical function in horses. The usual doses of dexamethasone and hydrocortisone preparations in equine practice were administered intramuscularly to six horses, and peripheral blood was collected at different time points. Concentrations of dexamethasone and hydrocortisone in the plasma, before and after drug administration, were measured using liquid chromatography-tandem mass spectrometry. Considering circadian rhythms in endogenous hydrocortisone levels, hormone concentrations, before and after drug administration, were compared at the same time of the day. Plasma dexamethasone concentrations were below the limit of quantification at 72 hr post-administration. Plasma hydrocortisone concentrations were significantly lower from 1 to 72 hr after administration. After hydrocortisone preparation administration, plasma hydrocortisone levels were significantly higher until 9 hr, and significantly lower at 24 and 48 hr. The suppression rate of endogenous hydrocortisone ranged over 2.2-5.3% with dexamethasone treatment and 17.5-45.7% with hydrocortisone treatment. The study clearly indicated the effects of glucocorticoids on adrenocortical function in horses and provided basic knowledge about the selection and prescription of glucocorticoid preparations and setting the withdrawal times in equine clinical setting.

Effect of Glucocorticoids on the Development of COVID-19-Associated Pulmonary Aspergillosis: A Meta-Analysis of 21 Studies and 4972 Patients

Effect of Glucocorticoids on the Development of COVID-19-Associated Pulmonary Aspergillosis: A Meta-Analysis of 21 Studies and 4972 Patients

The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages.

Synthetic glucocorticoids are used to treat many chronic and acute inflammatory conditions. Frequent adverse effects of prolonged exposure to glucocorticoids include disturbances of glucose homeostasis caused by changes in glucose traffic and metabolism in muscle, liver, and adipose tissues. Macrophages are important targets for the anti-inflammatory actions of glucocorticoids. These cells rely on aerobic glycolysis to support various pro-inflammatory and antimicrobial functions. Employing a potent pro-inflammatory stimulus in two commonly used model systems (mouse bone marrow-derived and human monocyte-derived macrophages), we showed that the synthetic glucocorticoid dexamethasone inhibited lipopolysaccharide-mediated activation of the hypoxia-inducible transcription factor HIF-1α, a critical driver of glycolysis. In both cell types, dexamethasone-mediated inhibition of HIF-1α reduced the expression of the glucose transporter GLUT1, which imports glucose to fuel aerobic glycolysis. Aside from this conserved response, other metabolic effects of lipopolysaccharide and dexamethasone differed between human and mouse macrophages. These findings suggest that glucocorticoids exert anti-inflammatory effects by impairing HIF-1α-dependent glucose uptake in activated macrophages. Furthermore, harmful and beneficial (anti-inflammatory) effects of glucocorticoids may have a shared mechanistic basis, depending on the alteration of glucose utilization.

The effects of glucocorticoid plus intravenous immunoglobulin (IVIG) vs IVIG alone on platelet activation in children with Kawasaki disease.

Even though intravenous immunoglobulin (IVIG) is a current treatment for Kawasaki disease (KD), 10-20% of patients require additional therapy. This study seeks to investigate the therapeutic effects of glucocorticoids plus IVIG on KD and to ascertain the subsequent effect on platelet activation during the acute phase. A total of 32 children with KD were randomly classified into two groups: the experimental group (16 cases) and the control group (16 cases). The control group was exposed to IVIG (2 g/kg), whereas children in the experimental group were treated with IVIG (2 g/kg) + glucocorticoid. Peripheral venous blood samples were obtained from all participants before treatment as well as three days post-treatment to test platelet activation levels with procaspase activating compound-1 (PAC-1) antibody, Toll-like receptor 4 (TLR4), interleukin-6 (IL- 6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and C-reactive protein (CRP). Fever duration posttreatment was documented for both groups. Additionally, the coronary arteries in both groups were evaluated during three months of treatment. After treatment, the experimental group had remarkably lower levels of TNF-α, CRP, PCT, IL-6, PAC- 1, and TLR4 relative to the control group. The fever persistence rate was considerably elevated in the control group compared to the experimental group (log-rank, P=0.024). In addition, the z-score of coronary artery size dropped after IVIG + glucocorticoids treatment compared to the control group, although this difference was not significant. The IVIG + glucocorticoids can quickly mitigate the inflammatory response and platelet activation. Moreover, it can also improve clinical symptoms in children with KD.

In vitro methods to assess 11β-hydroxysteroid dehydrogenase type 1 activity.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive 11-keto-glucocorticoids to their active 11β-hydroxylated forms. It also catalyzes the oxoreduction of other endogenous and exogenous substrates. The ubiquitously expressed 11β-HSD1 shows high levels in liver and other metabolically active tissues such as brain and adipose tissue. Pharmacological inhibition of 11β-HSD1 was found to ameliorate adverse metabolic effects of elevated glucocorticoids in rodents and humans, improve wound healing and delay skin aging, and enhance memory and cognition in rodent Alzheimer's disease models. Thus, there is an interest to develop 11β-HSD1 inhibitors for therapeutic purposes. This chapter describes in vitro methods to assess 11β-HSD1 enzyme activity for different purposes, be it in disease models, for the assessment of the kinetics of novel substrates or for the screening and characterization of inhibitors. 11β-HSD1 protein expression and preparations of the different biological samples are discussed first, followed by a description of a well-established and easily adaptable 11β-HSD1 enzyme activity assay. Finally, different readout methods are shortly described. This chapter should provide the reader with a toolbox of methods to assess 11β-HSD1 activity with instructions in the form of a decision tree for the choice and implementation of an appropriate enzyme activity assay.

The m6A demethylase FTO promotes keloid formation by up-regulating COL1A1.

Keloid is a dermal fibrotic disease characterized by excessive proliferation of dermal fibroblasts and deposition of excessive collagen. N6-methyladenosine (m6A) plays a significant role in numerous physiological and pathological regulatory processes in the human body. Fat mass and obesity-associated protein (FTO) is one of the most essential m6A demethylases. However, whether FTO has a regulatory role in keloid development remains to be determined. In this study, we investigated the effects of the m6A demethylase FTO on keloid formation by performing hematoxylin and eosin (H&E) staining, m6A dot blotting, transwell migration experiment, and methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP-qPCR) tests, as well as real-time PCR (RT-PCR) and Western blot assays. The H&E staining indicated abnormal arrangement and proliferation of fibroblasts in the keloid tissue. The m6A dot blotting and qPCR revealed lower levels of m6A modification and increased expression of the m6A demethylases FTO in keloid tissue. Furthermore, overexpression of FTO promoted fibroblast migration as well as the expression of collagen type I alpha 1 chain (COL1A1) and α-smooth muscle actin (α-SMA). Mechanistic experiments demonstrated that FTO enhances keloid formation by modulating COL1A1 m6A modification and messenger RNA (mRNA) stability. In addition, this study also revealed the role of FTO in the therapeutic effect of glucocorticoids on keloids. Our study demonstrates that FTO upregulates COL1A1 expression via regulating COL1A1 m6A modification and maintaining mRNA stability, hence promoting keloid development and providing a potential new therapeutic target for the treatment of keloids.

Genomic and non-genomic effects of glucocorticoids in respiratory diseases.

Cortisol is an endogenous steroid hormone essential for the natural resolution of inflammation. Synthetic glucocorticoids (GCs) were developed and are currently amongst the most widely prescribed anti-inflammatory drugs in our modern clinical landscape owing to their potent anti-inflammatory activity. However, the extent of GC's effects has yet to be fully elucidated. Indeed, GCs modulate a broad spectrum of cellular activity, from their classical regulation of gene expression to acute non-genomic mechanisms of action. Furthermore, tissue specific effects, disease specific conditions, and dose-dependent responses complicate their use, with side-effects potentially plaguing their use. It is thus vital to outline and consolidate the effects of GCs, to demystify and maximize their therapeutic potential while avoiding pitfalls that would otherwise render them obsolete.

Retracted: Meta-Analysis of the Effect of Glucocorticoids on Adult Acute Respiratory Distress Syndrome.

[This retracts the article DOI: 10.1155/2022/4020489.].

Glucocorticoid Effects on Proteoglycans and Glycosaminoglycans.

Glucocorticoids are steroid hormones that play diverse roles in numerous normal and pathological processes. They are actively used to treat a wide variety of diseases, including neurodegenerative and inflammatory diseases, cancers, and COVID-19, among others. However, the long-term use of glucocorticoids is associated with numerous side effects. Molecular mechanisms of these negative side effects are not completely understood. Recently, arguments have been made that one such mechanisms may be related to the influence of glucocorticoids on O-glycosylated components of the cell surface and extracellular matrix, in particular on proteoglycans and glycosaminoglycans. The potential toxic effects of glucocorticoids on these glycosylated macromolecules are particularly meaningful for brain physiology because proteoglycans/glycosaminoglycans are the main extracellular components of brain tissue. Here, we aim to review the known effects of glucocorticoids on proteoglycan expression and glycosaminoglycan content in different tissues, with a specific focus on the brain.

Neuroendocrine mechanisms in oxaliplatin-induced hyperalgesic priming.

Stress plays a major role in the symptom burden of oncology patients and can exacerbate cancer chemotherapy-induced peripheral neuropathy (CIPN), a major adverse effect of many classes of chemotherapy. We explored the role of stress in the persistent phase of the pain induced by oxaliplatin. Oxaliplatin induced hyperalgesic priming, a model of the transition to chronic pain, as indicated by prolongation of hyperalgesia produced by prostaglandin E 2 , in male rats, which was markedly attenuated in adrenalectomized rats. A neonatal handling protocol that induces stress resilience in adult rats prevented oxaliplatin-induced hyperalgesic priming. To elucidate the role of the hypothalamic-pituitary-adrenal and sympathoadrenal neuroendocrine stress axes in oxaliplatin CIPN, we used intrathecally administered antisense oligodeoxynucleotides (ODNs) directed against mRNA for receptors mediating the effects of catecholamines and glucocorticoids, and their second messengers, to reduce their expression in nociceptors. Although oxaliplatin-induced hyperalgesic priming was attenuated by intrathecal administration of β 2 -adrenergic and glucocorticoid receptor antisense ODNs, oxaliplatin-induced hyperalgesia was only attenuated by β 2 -adrenergic receptor antisense. Administration of pertussis toxin, a nonselective inhibitor of Gα i/o proteins, attenuated hyperalgesic priming. Antisense ODNs for Gα i 1 and Gα o also attenuated hyperalgesic priming. Furthermore, antisense for protein kinase C epsilon, a second messenger involved in type I hyperalgesic priming, also attenuated oxaliplatin-induced hyperalgesic priming. Inhibitors of second messengers involved in the maintenance of type I (cordycepin) and type II (SSU6656 and U0126) hyperalgesic priming both attenuated hyperalgesic priming. These experiments support a role for neuroendocrine stress axes in hyperalgesic priming, in male rats with oxaliplatin CIPN.

Роль метаболизма кортизола в реализации патогенетических звеньев развития осте- опороза – обоснование поиска новых фар- макотерапевтических мишеней (обзор)

Background: Osteoporosis is an important medical and social public health problem in an aging or elderly society. Osteoporosis is caused by an imbalance in bone remodeling, which is a continuous process of destruction of mature bone tissue by osteoclasts (bone resorption) and the formation of new bone tissue by osteoblasts (bone formation). The system of bone homeostasis that regulates the functional activity of osteoclasts and osteoblasts is represented by a wide range of molecules. The understanding of the molecular mechanisms of bone homeostasis achieved today makes it possible to significantly change and expand the paradigms of treatment and prevention of osteoporosis. The aim of the study: To consider the main pathogenetic pathways through which the effect of the cortisol metabolism system on the development of osteoporosis is realized and to identify ways to find new therapeutic approaches to the treatment and prevention of this pathology. Materials and methods: To achieve this goal, we analyzed the literature on the influence of cortisol metabolism on the development of osteoporosis published in the last 10 years. Results: To date, there are significant prerequisites in the literature for a direct connection of disorders of steroid hormone metabolism with the development of osteoporosis and a violation of osteoreparative processes. This literature review presents the main pathogenetic pathways that cause the processes leading to a decrease in bone density in disorders of cortisol metabolism. The enzyme 11b-hydroxysteroid dehydrogenase (11b-HSD), represented by two isoforms, performs the mutual conversion of cortisone and cortisol in tissues. Using the methods of reverse genetics, we have established the systemic consequences of knockout of both isoforms. Convincing evidence demonstrates that both enzymes are involved in the pathogenesis of osteoporosis. Since animals with type 11b-HSD deficiency are characterized by proinflammatory activation of the endothelium, we assume that further study of the interaction between the endothelium and bone tissue is of particular interest. Conclusion: The effects of glucocorticoids on eNOS expression seem to be significantly modulated by 11ß-HSD isoenzymes. The established relationship between 11ß-HSD and NO can be considered a promising pharmacotherapeutic target. In this regard, a pharmacotherapeutic approach aimed at restoring the balance of nitric oxide in bone and endothelial tissues, currently considered as one of the most relevant ways to correct osteoporosis, may also be relevant in case of cortisol metabolism disorders due to 11ß-HSD2 deficiency.

Comparison of effects of aminosalicylic acid, glucocorticoids and immunosuppressive agents on the expression of multidrug-resistant genes in ulcerative colitis

To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressants on the expression levels of multidrug resistance genes in patients with ulcerative colitis (UC), with the aim of providing a theoretical and therapeutic basis for the diagnosis, treatment, and prevention of UC. Fresh colonic mucosal tissues or postoperative pathological biopsies from 148 UC patients were collected, and the distribution sites and morphology of P-glycoprotein (P-gp) were detected using immunohistochemical staining. RT-PCR was used to quantify the expression levels of multidrug resistance gene (MDR1) mRNA before and after the corresponding treatment, and the effects of aminosalicylic acid, glucocorticoids and immunosuppressive drugs on P-gp were compared. In addition, the effects of the three drugs on MDR1 mRNA were analyzed. Administration of 5-aminosalicylic acid (5-ASA) drugs did not correlate with MDR1 expression in UC, whereas administration of glucocorticoids and immunosuppressive drugs was positively correlated with MDR1 expression profile. The expression levels of MDR1 mRNA and its product P-gp were significantly upregulated in patients who did not respond to glucocorticoids and immunosuppressive drugs. 5-ASA had no effect on the expression levels of MDR1 and its product P-gp in patients with a confirmed diagnosis of UC. However, the use of glucocorticoids and immunosuppressants can increase the expression level of MDR1.

Transcriptional glucocorticoid effects in the brain: Finding the relevant target genes.

Glucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many glucocorticoid effects depend on the modulation of gene transcription, it is a major challenge to link gene expression to function given the large-scale, apparently pleiotropic genomic responses. The extensive sets of MR and GR target genes are highly specific per cell type, and the brain contains many different (neuronal and non-neuronal) cell types. Next to the set "trait" of cellular context, the "state" of other active signaling pathways will affect MR and GR transcriptional activity. Here, we discuss receptor specificity and contextual factors that determine the transcriptional outcome of MR/GR signaling, experimental possibilities offered by single-cell transcriptomics approaches, and reflect on how to make sense of lists of target genes in relation to understanding the functional effects of steroid receptor activation.

Effects of Glucocorticoids in Murine Models of Duchenne and Limb-Girdle Muscular Dystrophy.

In vivo testing of glucocorticoid steroids in dystrophic mice offers important insights in benefits and risks of those drugs in the pathological context of muscular dystrophy. Frequency of dosing changes the spectrum of glucocorticoid effects on muscle and metabolic homeostasis. Here, we describe a combination of non-invasive and invasive methods to quantitatively discriminate the specific effects of intermittent (once-weekly) versus mainstay (once-daily) regimens on muscle fibrosis, muscle function, and metabolic homeostasis in murine models of Duchenne and limb-girdle muscular dystrophies.

Glucocorticoid effects on working memory impairment require l-type calcium channel activity within prefrontal cortex

Previous findings have indicated that glucocorticoid hormones impair working memory via an interaction with the β-adrenoceptor-cAMP signaling cascade to rapidly increase cAMP-dependent protein kinase (PKA) activity within the prefrontal cortex (PFC). However, it remains elusive how such activation of PKA can affect downstream cellular mechanisms in regulating PFC cognitive function. PKA is known to activate l-type voltage-gated Ca2+ channels (LTCCs) which regulate a broad range of cellular processes, including neuronal excitability and neurotransmitter release. The present experiments examined whether LTCC activity within the PFC is required in mediating glucocorticoid and PKA effects on spatial working memory. Male Sprague Dawley rats received bilateral administration of the LTCC inhibitor diltiazem together with either the glucocorticoid receptor agonist RU 28362 or PKA activator Sp-cAMPS into the PFC before testing on a delayed alternation task in a T-maze. Both RU 28362 and Sp-cAMPS impaired working memory, whereas the LTCC inhibitor diltiazem fully blocked the working memory impairment induced by either RU 28362 or Sp-cAMPS. Conversely, bilateral administration of the LTCC agonist Bay K8644 into the PFC was sufficient to impair working memory. Thus, these findings provide support for the view that glucocorticoids, via an interaction with the β-adrenergic signaling cascade and enhanced PKA activity levels, impair working memory by increasing LTCC activity in the PFC.