Abstract
Purpose :
The links between exogenous glucocorticoids and central serous chorioretinopathy (CSCR) remain undefined. We previously treated Lewis rats with systemic dexamethasone, and observed low intraocular corticosterone levels, and an imbalance towards MR pathway activation in the RPE-choroid complex. We also showed that in the ocular steroidome of patients with chronic inactive CSCR cortisol levels were lower than in controls. The aim of this study is to assess the impact of oral eplerenone combined with systemic dexamethasone treatment in the RPE-choroid complex and ocular steroid metabolism of Lewis rats.
Methods :
Lewis rats were untreated (n=4), received daily subcutaneous injection of dexamethasone (dexa group, 1 mg/kg/day; N=16), and had oral eplerenone with their food (dexa-eple group, 200mg/kg; n=6) for 7 days. The full steroidome was quantified in sera and intraocular fluids at baseline and at day 8, using an LC-MS/MS method. The expression level of Nr3c1 (GR), Nr3c2 (MR), 11β-hsd1, 11β-hsd2 and mineralocorticoid-induced genes were measured in ocular tissues.
Results :
At day 8, intraocular corticosterone concentrations were 5±2ng/mL in the control group, 0.001±0.0005ng/mL in the dexa group, and 0.7±0.1ng/mL in the dexa-eple group. Corticosterone significantly increased in the dexa-eple group compared to dexa (p<0.001). In the RPE-choroid, HSD2 expression increased in the dexa group compared to baseline (2,4±0,48vs1±0,44 fold-change, p<0.01). and decreased in the dexa-eple group compared to dexa (0,23±0,2vs.2,4±0,48 fold-change, p<0.001). Ngal, Plaur and PTX3 expressions were significantly reduced in the dexa-eple group compared to the dexa group (0,4±0,11vs.5,7±0,9 fold-change p<0.0001; 0,01vs. 2,4±0,3 fold-change p<0.0001; 1,9±0,4vs.1,2±0,1fold-change p<0.01). Intraocular aldosterone levels were undetectable, whilst systemic aldosterone significantly increased in the dexa group (0,1±0,05 ng/ml, p<0,01).
Conclusions :
Dexamethasone treatment induced HPA axis brake, and disrupted the MR-GR balance in the RPE-choroid complex of rats with a reduction of intraocular glucocorticoids, similar to what observed in patients with CSCR. In rats, this imbalance was directed towards an MR activation, and oral administration of an MR antagonist partially compensated it by preventing MR-aldosterone binding, by limiting MR-regulated genes activation, and by increasing intraocular glucocorticoids concentrations.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.