Therapeutic Mechanisms of Glucocorticoids

Vandewalle, Jolien; Luypaert, Astrid; Bosscher, Karolien De; Libert, Claude

doi:10.1016/j.tem.2017.10.010

Cited by 411 publications

(338 citation statements)

References 90 publications

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“…Of interest, even without an MCAO insult, GR siRNA treated animals demonstrated a significant increase in key pro-inflammatory genes, IL-6, IL-1β, TNF-α, in the brain, indicating that the GR repression impaired normally negative regulation of GR on pro-inflammatory genes and primed the brain in a pre-inflammatory state. This is consistent with the well-documented anti-inflammatory effects of GR [24,28,29]. Of critical importance, GR repression in the brain significantly heightened the inflammatory response induced by the MCAO challenge.…”

Section: Discussionsupporting

confidence: 89%

Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice

Huang

et al. 2018

IJMS

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Strokes are one of the leading causes of mortality and chronic morbidity in the world, yet with only limited successful interventions available at present. Our previous studies revealed the potential role of the glucocorticoid receptor (GR) in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). In the present study, we investigate the effect of GR knockdown on acute ischemic brain injuries in a model of focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) in adult male CD1 mice. GR siRNAs and the negative control were administered via intracerebroventricular (i.c.v.) injection 48 h prior to MCAO. The cerebral infarction volume and neurobehavioral deficits were determined 48 h after MCAO. RT-qPCR was employed to assess the inflammation-related gene expression profiles in the brain before and after MCAO. Western Blotting was used to evaluate the expression levels of GR, the mineralocorticoid receptor (MR) and the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling. The siRNAs treatment decreased GR, but not MR, protein expression, and significantly enhanced expression levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in the brain. Of interest, GR knockdown suppressed BDNF/TrkB signaling in adult mice brains. Importantly, GR siRNA pretreatment significantly increased the infarction size and exacerbated the neurobehavioral deficits induced by MCAO in comparison to the control group. Thus, the present study demonstrates the important role of GR in the regulation of the inflammatory responses and neurotrophic BDNF/TrkB signaling pathway in acute ischemic brain injuries in adult mice, revealing a new insight into the pathogenesis and therapeutic potential in acute ischemic strokes.

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Section: Discussionsupporting

confidence: 89%

Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice

Huang

et al. 2018

IJMS

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“…8 This synthetic glucocorticoid has many clinical applications, for example, as an anti-inflammatory agent, for pain management, in tumor therapies, and for use in autoimmune diseases. 9 Initial studies showed that Dex released from scaffold materials in vivo was able to enhance bone formation. 10 However, the side effects of long-term corticosteroid-treatments, in particular, the development of glucocorticoid-induced osteoporosis (GIOP), must not be neglected.…”

Section: Introductionmentioning

confidence: 99%

Sulfated hyaluronic acid and dexamethasone possess a synergistic potential in the differentiation of osteoblasts from human bone marrow stromal cells

Schmidt

Vogel

Moeller

et al. 2018

J of Cellular Biochemistry

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The development of novel bioactive biomaterials is urgently needed to meet the needs of an aging population. Both sulfated hyaluronic acid and dexamethasone are candidates for the functionalization of bone grafts, as they have been shown to enhance the differentiation of osteoblasts from bone marrow stromal cells in vitro and in vivo. However, the underlying mechanisms are not fully understood. Furthermore, studies combining different approaches to assess synergistic potentials are rare. In this study, we aim to gain insights into the mode of action of both sulfated hyaluronic acid and dexamethasone by a comprehensive analysis of the cellular fraction, released matrix vesicles, and the extracellular matrix, combining classical biochemical assays with mass spectrometry–based proteomics, supported by novel bioinformatical computations. We found elevated differentiation levels for both treatments, which were further enhanced by a combination of sulfated hyaluronic acid and dexamethasone. Single treatments revealed specific effects on osteogenic differentiation. Dexamethasone activates signalling pathways involved in the differentiation of osteoblasts, for example, CXC‐motif chemokine receptor type 4 and mitogen‐activated protein kinases. The effects of sulfated hyaluronic acid were predominantly linked to an alteration in the composition of the extracellular matrix, affecting the synthesis, secretion, and/or activity of fibrillary (fibronectin and thrombospondin‐2) and nonfibrillary (transglutaminase‐2, periostin, and lysyloxidase) extracellular matrix components, including proteases and their inhibitors (matrix metalloproteinase‐2, tissue inhibitor of metalloproteinase‐3). The effects were treatment specific, and less additive or contrary effects were found. Thus, we anticipate that the synergistic action of the treatment‐specific effects is the key driver in elevated osteogenesis.

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“…By combining GR with PPARα stimulation, their antiinflammatory effects might be additive, but not their side effects. 15…”

Section: Complementary Ther Apie Smentioning

confidence: 99%

Therapeutic utility of glucocorticoids and antihistamines cotreatment. Rationale and perspectives

Zappia

Monczor

2019

Pharmacology Res & Perspec

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Antihistamines and glucocorticoids (GCs) are often used together in the clinic, in several inflammatory‐related situations. Even though there is no clear rationale for this drug association, the clinical practice is based on the assumption that due to their concomitant antiinflammatory effects, there should be an intrinsic benefit in their coadministration. Our group has studied the molecular interaction between the histamine H1 receptor and the glucocorticoid receptor (GR) signaling pathways, showing an enhancing effect on GC‐induced GR transcriptional activity induced by antihistamines. We hypothesize that the existence of this synergistic effect could contribute in reducing the GCs clinical doses, ineffective by itself but effective in combination with an antihistamine. This could result in a therapeutic advantage as the GC‐desired effects may be reinforced by the addition of an antihistamine and, as a consequence of the dose reduction, GC‐related adverse effects could be reduced or at least mitigated. Here we discuss the potential therapeutic applications of this cotreatment seeking to evaluate its usefulness, especially in inflammatory‐related conditions.

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Therapeutic Mechanisms of Glucocorticoids

Cited by 411 publications

References 90 publications

Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice

Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice

Sulfated hyaluronic acid and dexamethasone possess a synergistic potential in the differentiation of osteoblasts from human bone marrow stromal cells

Therapeutic utility of glucocorticoids and antihistamines cotreatment. Rationale and perspectives

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