Mifepristone Blocks Specific Glucocorticoid Receptor Binding in Rabbit Iris—Ciliary Body

Munden, Paul M.; Schmidt, Thomas J.

doi:10.1001/archopht.1992.01080170125039

Cited by 5 publications

(2 citation statements)

References 13 publications

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“…A possible animal model for these experiments appears to be the New Zealand white albino rabbit (NZWAR). This is an established model for the investigation of corneal disease (Nakamura et al 2003, Tungsiripat et al 2003, Ivarsen et al 2004, Mimura et al 2005 and AH dynamics (Tsukahara et al 1986, Green et al 1989, Munden & Schmidt 1992, Lim et al 2005. The corticosteroid hormone profile is similar to humans (i.e.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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The prereceptor regulation of glucocorticoids (GCs) by 11b-hydroxysteroid dehydrogenase type-1 (11b-HSD1), a bidirectional isozyme that interconverts active (cortisol) and inactive (cortisone) GCs, is an established determinant of GC function in tissues such as liver, adipose and bone. Although the therapeutic use of GCs is abundant in ophthalmic practice, where GC interactions with nuclear receptors modulate gene transcription, the prereceptor regulation of endogenous cortisol is not well described in ocular tissues. Recent descriptive studies have localised 11b-HSD1 to the human corneal epithelium and non-pigmented epithelium (NPE) of the ciliary body, indicating a link to corneal epithelial physiology and aqueous humour production. In this study, we characterise the functional aspects of the autocrine regulation of GCs in the anterior segment of the rabbit eye. Using our in-house generated primary antibody to human 11b-HSD1, immunohistochemical analyses were performed on paraffin-embedded sections of whole New Zealand white albino rabbits, (NZWAR) eyes. As in human studies, 11b-HSD1 was localised to the corneal epithelium and the NPE. No staining was seen in the albino 'pigmented' ciliary epithelium. Specific enzyme assays for oxo-reductase (cortisone/cortisol) and dehydrogenase (cortisol/cortisone) activity indicated predominant 11b-HSD1 oxo-reductase activity from both the intact ciliary body tissue (nZ12, median 2$1 pmol/mg per h and range 1$25-2$8 pmol/mg per h; PZ0$006) and primary cultures of corneal epithelial cells (nZ12, median 3$0 pmol/mg per h and range 1$0-7$4 pmol/mg per h, PZ0$008) compared with dehydrogenase activity (median 1$0 pmol/mg per h and range 0$5-2$0 pmol/mg per h; median 0$5 pmol/mg per h and range 0$25-1$9 pmol/mg per h respectively). These findings were supported by expression of 11b-HSD1 protein as visualised by Western blotting of ciliary body tissue and immunocytochemistry of corneal epithelial cells. Reduction of corneal epithelial cell proliferation was seen after primary cultures were co-incubated with cortisol and cortisone. 11b-HSD1 activity was not demonstrated in naïve conjunctival fibroblasts or corneal stromal keratocytes. Our results indicate that the distribution of 11b-HSD1 in the rabbit resembles that of the human eye and activates cortisone to cortisol in both corneal and uveal tissues. The NZWAR provides a suitable in vivo model for the further evaluation of 11b-HSD1 activity in the eye, especially its role in corneal epithelial and ciliary body physiology.

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Section: Introductionmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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“…To block the MR, 600mg spironolactone (Aldactone provided by The Apothecary Shoppe, Tulsa, OK) was used ( Delyani, 2000 ), while to block the GR, 600mg mifepristone (Mifeprex provided by Athenium Pharmaceuticals, LLC, New York, NY) was selected ( Munden and Schmidt, 1992 ). A placebo was also used (provided by The Apothecary Shoppe).…”

Section: Methodsmentioning

confidence: 99%

The Effect of Mineralocorticoid and Glucocorticoid Receptor Antagonism on Autobiographical Memory Recall and Amygdala Response to Implicit Emotional Stimuli

Young

Preskorn

Victor

et al. 2016

IJNPPY

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Background:Acutely elevated cortisol levels in healthy humans impair autobiographical memory recall and alter hemodynamic responses of the amygdala to emotionally valenced stimuli. It is hypothesized that the effects of the cortisol on cognition are influenced by the ratio of mineralocorticoid receptor to glucocorticoid receptor occupation. The current study examined the effects of acutely blocking mineralocorticoid receptors and glucocorticoid receptors separately on 2 processes known to be affected by altering levels of cortisol: the specificity of autobiographical memory recall, and the amygdala hemodynamic response to sad and happy faces.Methods:We employed a within-subjects design in which 10 healthy male participants received placebo, the mineralocorticoid receptor antagonist spironolactone (600mg) alone, and the glucocorticoid receptor antagonist mifepristone (600mg) alone in a randomized, counter-balanced order separated by 1-week drug-free periods.Results:On autobiographical memory testing, mineralocorticoid receptor antagonism impaired, while glucocorticoid receptor antagonism improved, recall relative to placebo, as evinced by changes in the percent of specific memories recalled. During fMRI, the amygdala hemodynamic response to masked sad faces was greater under both mineralocorticoid receptor and glucocorticoid receptor antagonism relative to placebo, while the response to masked happy faces was attenuated only during mineralocorticoid receptor antagonism relative to placebo.Conclusions:These data suggest both mineralocorticoid receptor and glucocorticoid receptor antagonism (and potentially any deviation from the normal physiological mineralocorticoid receptor/glucocorticoid receptor ratio achieved under the circadian pattern) enhances amygdala-based processing of sad stimuli and may shift the emotional processing bias away from the normative processing bias and towards the negative valence. In contrast, autobiographical memory was enhanced by conditions of reduced glucocorticoid receptor occupancy.

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Clinical and pharmacological aspects of accidental triamcinolone acetonide overdosage: a case study

Schweitzer

Lebrun

Krishnaswami

et al. 2000

The Netherlands Journal of Medicine

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Mifepristone Blocks Specific Glucocorticoid Receptor Binding in Rabbit Iris—Ciliary Body

Cited by 5 publications

References 13 publications

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

The Effect of Mineralocorticoid and Glucocorticoid Receptor Antagonism on Autobiographical Memory Recall and Amygdala Response to Implicit Emotional Stimuli

Clinical and pharmacological aspects of accidental triamcinolone acetonide overdosage: a case study

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