ABSTRACT
Choroidal neovascularization (CNV) is a major cause of visual impairment in patients suffering from wet age-related macular degeneration (AMD), particularly when refractory to intraocular anti-VEGF injections. Here we report that treatment with the oral mineralocorticoid receptor (MR) antagonist spironolactone reduces signs of CNV in patients refractory to anti-VEGF treatment. In animal models of wet AMD, pharmacological inhibition of the MR pathway or endothelial-specific deletion of MR inhibits CNV through VEGF-independent mechanisms, in part through upregulation of the extracellular matrix protein decorin. Intravitreal injections of spironolactone-loaded microspheres and systemic delivery lead to similar reductions in CNV. Together, our work suggests MR inhibition as a novel therapeutic option for wet AMD patients unresponsive to anti-VEGF drugs.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Choroidal Neovascularization/drug therapy , Macular Degeneration/drug therapy , Mineralocorticoid Receptor Antagonists/therapeutic use , Receptors, Mineralocorticoid/genetics , Spironolactone/therapeutic use , Aged , Aged, 80 and over , Animals , Choroid/drug effects , Choroid/metabolism , Choroid/pathology , Choroidal Neovascularization/genetics , Choroidal Neovascularization/metabolism , Choroidal Neovascularization/pathology , Drug Compounding/methods , Female , Gene Expression , Humans , Intravitreal Injections , Macular Degeneration/genetics , Macular Degeneration/metabolism , Macular Degeneration/pathology , Male , Mice , Mice, Transgenic , Microspheres , Pilot Projects , Prospective Studies , Ranibizumab/therapeutic use , Rats, Long-Evans , Receptors, Mineralocorticoid/metabolism , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Mineralocorticoid receptor (MR) contributes to retinal/choroidal homeostasis. Excess MR activation has been shown to be involved in pathogenesis of central serous chorioretinopathy (CSCR). Systemic administration of MR antagonist (MRA) reduces subretinal fluid and choroidal vasodilation, and improves the visual acuity in CSCR patients. To achieve long term beneficial effects in the eye while avoiding systemic side-effects, we propose the use of biodegradable spironolactone-loaded poly-lactic-co-glycolic acid (PLGA) microspheres (MSs). In this work we have evaluated the ocular tolerance of MSs containing spironolactone in rat' eyes. As previous step, we have also studied the tolerance of the commercial solution of canrenoate salt, active metabolite of spironolactone. PLGA MSs allowed in vitro sustained release of spironolactone for 30days. Rat eyes injected with high intravitreous concentration of PLGA MSs (10mg/mL) unloaded and loaded with spironolactone maintained intact retinal lamination at 1month. However enhanced glial fibrillary acidic protein immunostaining and activated microglia/macrophages witness retinal stress were observed. ERG also showed impaired photoreceptor function. Intravitreous PLGA MSs concentration of 2mg/mL unloaded and loaded with spironolactone resulted well tolerated. We observed reduced microglial/macrophage activation in rat retina compared to high concentration of MSs with normal retinal function according to ERG. Spironolactone released from low concentration of MSs was active in the rat retina. Low concentration of spironolactone-loaded PLGA MSs could be a safe therapeutic choice for chorioretinal disorders in which illicit MR activation could be pathogenic.
