Abstract
Purpose :
Chronic systemic dexamethasone in Lewis rats breaks the HPA axis, reducing systemic and intraocular corticosterone, and pushing the MR/GR receptor balance in RPE/choroid towards MR.
The present study reports the effects of a systemic MR-antagonist administration, in parallel with dexamethasone-induced HPA axis brake, on the intraocular MR/GR balance and on the systemic and intraocular concentrations of their ligands.
Methods :
Lewis rats were untreated (n=2) or received daily injections of either dexamethasone (1 mg/kg/day; n=6), dexamethasone and spironolactone (25mg/kg; n=6) or diluted saline (n=6) daily for 5 days. The full steroidome was quantified in sera and intraocular fluids at baseline and at day 5, using a specific and highly sensitive Lc-MS/MS validated method. The expression level of Nr3c1 (GR), Nr3c2 (MR), 11β-hsd1, 11β-hsd2 and mineralocorticoid-induced genes were measured in ocular tissues.
Results :
Spironolactone increased systemic corticosterone at day 5 as compared to the dexamethasone group (4,18 ± 1,9 vs. 2,33 ± 0,7 ng/mL, p=0,04, respectively). 11-dehydrocorticosterone mean levels were reduced in the dexamethasone and saline group (27 ± 6,0 vs. 0,7 ± 0,2 ng/mL, p=0,03 and 27 ± 2,5 vs. 18 ± 6,4 ng/mL, p=0,03, respectively) at day 5 compared to baseline. Intraocular levels of both ligands were positively correlated to their systemic circulating levels (r=0,95, p<0,001 and r=0,96, p<0,001, respectively). In the RPE/choroid complex, spironolactone significantly reduced the MR/GR ratio (2,51 ± 0,49 vs. 8,42 ± 3,1, p<0,001), and decreased the MR-activated genes Shroom2 (0,76 ± 0,27 fold-change, p=0,01) and Plaur (1,05 ± 0,49 vs. 1,84 ± 0,58 fold-change, p=0,005) compared to the dexamethasone group, favoring GR activation.
Circulating aldosterone increased in all treatment groups at day 5 compared to baseline (dexamethasone 0,31 ± 0,03 vs. 0,10 ± 0,05 ng/mL, p<001; spironolactone 0,48 ± 0,16 vs. 0,11 ± 0,03 ng/mL, p=0,002; saline 0,3 ± 0,07 vs. 0,11 ± 0,03 ng/mL, p<0,001). Intraocular levels of aldosterone were below detectable levels.
Conclusions :
Systemic spironolactone partially compensates the hypocortisolaemia due to HPA axis brake and restores the MR/GR imbalance induced by the brake. But spironolactone increased significantly circulating aldosterone levels suggesting that local delivery would be more adapted to treat ocular diseases.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.