The effects of dexamethasone therapy on permeability, blood flow and iNOS expression in experimental glioma

Swaroop, G; Kelly, Paul A.; Holmes, Megan C.; Shinoda, Jun; Whittle, Ian R.

doi:10.1054/jocn.2000.0817

Cited by 10 publications

(6 citation statements)

References 19 publications

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“…Through up-regulation of these K + channel types, DEX could regulate transcellular pathways of brain tumor microvessels controlling BBB permeability. Although DEX seems to reduce oedema formation by modifying the permeability of capillaries within the tumor and enhancing the clearance of extracellular water (Swaroops et al, 2001; Sinha et al, 2004), the mechanisms of its actions are as to date not fully understood.…”

Section: Management Of Brain Oedema With Dexmentioning

confidence: 99%

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Cenciarini

Valentino

Belia

et al. 2019

Front. Mol. Neurosci.

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Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.

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Section: Management Of Brain Oedema With Dexmentioning

confidence: 99%

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Cenciarini

Valentino

Belia

et al. 2019

Front. Mol. Neurosci.

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“…Although their modes of action are poorly understood, steroids are thought to play a major role in decreasing oedema formation by reducing the permeability of neoplastic capillaries and/or enhancing the clearance of extracellular water. 3 The effects of glucocorticoids on water abnormalities in peritumoural brain can be assessed non invasively using diffusion tensor magnetic resonance imaging (DT-MRI). This technique permits the spatial mapping of the apparent diffusion tensor of water (D) in the brain, from which the mean diffusivity (,D.) and scalar diffusion anisotropy indices, such as the fractional anisotropy (FA), can be determined.…”

mentioning

confidence: 99%

Effects of dexamethasone on peritumoural oedematous brain: a DT-MRI study

Sinha

Bastin²,

Wardlaw³

et al. 2004

Journal of Neurology, Neurosurgery & Psychiatry

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Objectives: Glucocorticoids (dexamethasone) are thought to reduce peritumoural brain oedema by decreasing the permeability of neoplastic capillaries and/or enhancing the clearance of extracellular water. Diffusion tensor magnetic resonance imaging (DT-MRI) was used to measure the water diffusion parameters of oedematous and normal brain in a group of patients with intracranial tumours before and after steroid treatment. Methods: Fifteen patients with intracranial tumours (seven with high-grade glioma, four with metastatic carcinoma and four with meningioma) were examined before and 48-72 h after dexamethasone treatment (16 mg/day). The mean diffusivity (,D.) and fractional anisotropy (FA) were measured for oedematous brain and apparently normal contralateral white matter before and after steroid therapy. Results: In all three patient groups there was a significant decrease in ,D. of oedematous brain after steroid treatment (p,0.01). There was no significant change in FA of oedematous brain after treatment in any of the three groups. There was also no significant change in either ,D. or FA of apparently normal contralateral white matter after treatment. Conclusion: These data indicate that dexamethasone produces a localised reduction in the magnitude of extracellular water molecule mobility, and hence water content, in peritumoural oedematous brain. Furthermore, the magnitude of these changes is similar for both intra-and extra-axial tumours.

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“…However, in C6 experimental tumors in the rat in vivo, iNOS mRNA (and protein) is induced and expressed in necrotic cells in the center of the tumor mass as well as in cells along the tumor‐brain interface. Administration of dexamethasone to these animals has a profound effect on iNOS mRNA expression, demonstrating that in an in vivo environment, dexamethasone can have major effects at the transcriptional level (Swaroop et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and activity in C6 glioma cells

Shinoda¹,

McLaughlin²,

Bell³

et al. 2003

Glia

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The synthetic glucocorticoid dexamethasone is routinely used to stabilize patients with malignant gliomas. One putative target for glucocorticoid action is inducible nitric oxide synthase (iNOS), which is produced by the tumor cells as well as the host immune cells. In this study, we characterize the stimulatory effects of lipopolysaccharide (LPS) and the cytokine, tumor necrosis factor-alpha (TNFalpha), as well as the inhibitory effect of glucocorticoids, on iNOS gene expression and activity in C6 glioma cells cultured in vitro. LPS significantly increased iNOS mRNA expression, peaking at 6 h, while nitrite formation increased with time up to 72 h. Although TNFalpha alone induced neither iNOS mRNA expression nor nitrite formation, it significantly potentiated the effect of LPS on both. iNOS activity induced by LPS with or without TNFalpha was dose-dependently inhibited by dexamethasone, reaching a maximum of approximately 83% inhibition. This was completely reversed by the addition of RU38486, an antagonist of glucocorticoid receptors (GR). Dexamethasone inhibited iNOS mRNA expression; however, the maximum inhibition obtained was only 10%. These results suggest that as for induction of iNOS activity in C6 cells in vitro, the stimulatory effect of LPS is mainly due to an action at the transcriptional level. TNFalpha does not have intrinsic inducing activity, but has potentiating effects at the transcriptional and possibly at the posttranscriptional levels in the presence of LPS. The inhibitory effect of dexamethasone is GR-mediated and is mainly due to action at the posttranscriptional level.

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The effects of dexamethasone therapy on permeability, blood flow and iNOS expression in experimental glioma

Cited by 10 publications

References 19 publications

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Effects of dexamethasone on peritumoural oedematous brain: a DT-MRI study

Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and activity in C6 glioma cells

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