Abstract
Central serous chorioretinopathy (CSCR) is a retinal disease affecting the retinal pigment epithelium (RPE) and the choroid. This is a recognized side-effect of glucocorticoids (GCs), administered through nasal, articular, oral and dermal routes. However, CSCR does not occur after intraocular GCs administration, suggesting that a hypothalamic-pituitary-adrenal axis (HPA) brake could play a role in the mechanistic link between CSCR and GS. The aim of this study was to explore this hypothesis. To induce HPA brake, Lewis rats received a systemic injection of dexamethasone daily for five days. Control rats received saline injections. Baseline levels of corticosterone were measured by Elisa at baseline and at 5 days in the serum and the ocular media and dexamethasone levels were measured at 5 days in the serum and ocular media. The expression of genes encoding glucocorticoid receptor (GR), mineralocorticoid receptors (MR), and the 11 beta hydroxysteroid dehydrogenase (HSD) enzymes 1 and 2 were quantified in the neural retina and in RPE/ choroid. The expression of MR target genes was quantified in the retina (Scnn1A (encoding ENac-α, Kir4.1 and Aqp4) and in the RPE/choroid (Shroom 2, Ngal, Mmp9 and Omg, Ptx3, Plaur and Fosl-1). Only 10% of the corticosterone serum concentration was measured in the ocular media. Corticosterone levels in the serum and in the ocular media dropped after 5 days of dexamethasone systemic treatment, reflecting HPA axis brake. Whilst both GR and MR were downregulated in the retina without MR/GR imbalance, in the RPE/choroid, both MR/GR and 11β-hsd2/11β-hsd1 ratio increased, indicating MR pathway activation. MR-target genes were upregulated in the RPE/ choroid but not in the retina. The psychological stress induced by the repeated injection of saline also induced HPA axis brake with a trend towards MR pathway activation in RPE/ choroid. HPA axis brake causes an imbalance of corticoid receptors expression in the RPE/choroid towards overactivation of MR pathway, which could favor the occurrence of CSCR.
Highlights
Licensee MDPI, Basel, Switzerland.Glucocorticoids (GC) remain amongst the most widely prescribed class of drugs in many fields of medicine for their potent anti-inflammatory effects
The ocular side effects, such as cataract [6] and glaucoma [7,8] have been recognized at early stages [9] and are still associated with both systemic and local routes and are not alleviated by synthetic GCs. Another less frequent ocular side-effect of GCs is central serous chorioretinopathy (CSCR), a chorioretinal disease characterized by the occurrence of serous retinal detachments (SRD) secondary to a focal disruption of the retinal pigment epithelium (RPE) barrier and often associated with detachments of the pigment epithelium (PED) and an increased choroidal thickness [10,11]
In saline injected rats, serum corticosterone dropped to 13 ± 2 ng/mL [10.1–14.5, n = 4], a level that was not significantly lower than baseline, and not significantly different from the corticosterone level at day 5 in rats treated with dexamethasone (p = 0.007) (Kruskal–Wallis test p < 0.0001, followed by Dunn’s comparisons) (Figure 1A)
Summary
Licensee MDPI, Basel, Switzerland.Glucocorticoids (GC) remain amongst the most widely prescribed class of drugs in many fields of medicine for their potent anti-inflammatory effects. The early recognition of the severe side effects induced by cortisol [1] has led to the development of synthetic or semi-synthetic cortisol derivates with increased anti-inflammatory effects and reduced mineralocorticoid side-effects [2]. Hypertension and hydro-sodium retention have been associated with the activation of the mineralocorticoid pathway [3] while beneficial. Anti-inflammatory effects have been associated with the activation of the glucocorticoid receptor, leading to the classical potency glucocorticoids classification table [3–5].
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