Metipranolol promotes structure and function of retinal photoreceptors in the rd10 mouse model of human retinitis pigmentosa

Abstract

Metipranolol is a β‐adrenergic receptor antagonist that is given orally for the treatment of hypertension and also applied topically to the cornea for treating glaucoma. It also inhibits nitrosative stress which has previously been shown to be the cause of cone photoreceptor death in retinitis pigmentosa. In this study, we tested the hypothesis that metipranolol protects photoreceptor structure and function in the mouse model rd10. At P35, compared with vehicle‐treated rd10 mice in which rod degeneration was nearly complete, rd10 mice given daily subcutaneous injections of 40 mg/kg of metipranolol had reduction in markers of nitrosative stress, fewer TUNEL‐positive cells, increased outer nuclear layer thickness, and substantially more staining for rhodopsin. This was accompanied by significantly higher mean scotopic and photopic electroretinogram b‐wave amplitudes indicating improved photoreceptor function. At P50, metipranolol‐treated rd10 mice had decreased 3‐nitrotyrosine staining in the retina, increased immunostaining for cone arrestin, a marker for cone photoreceptors, and significantly higher scotopic and photopic b‐wave amplitudes at the highest stimulus intensity compared with vehicle‐treated mice. At P65, cone density was significantly higher in metipranolol‐treated versus vehicle‐injected rd10 mice. Metipranolol applied as eye drops promoted cone photoreceptor function in retinas of rd10 mice greater than subcutaneously injected metipranolol. The reduced nitrosative damage and rescue of functional loss of photoreceptors in rd10 mice suggests that metipranolol, a drug with established ocular safety and tolerability, may have potential for treating patients with retinitis pigmentosa.

Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

“…In the rd10 model of RP, the BAR antagonist metipranolol efficiently counteracts retinal damage by reducing nitrosative stress, which contributes to cone cell death [ 11 ]. In order to increase the understanding of the mechanisms underlying the efficacy of BAR blockade, here we demonstrate that the sympathetic system is overstimulated in the rd10 retina.…”

“…In the rd10 model, the BAR1/2 blocker metipranolol prevents the nitrosative damage induced by the reaction between nitric oxide and oxygen free radicals, which leads to cone death [ 11 ]. Metipranolol is also known to decrease retinal cell death through reduced nitrosative stress in additional models of retinal degeneration [ 40 ].…”

“…Recently, attention has been paid to the study of the role of the noradrenergic system in ocular diseases in which stress plays an important role through the release of catecholamines acting at beta adrenergic receptors (BARs). Preclinical evidence demonstrates that both rd10 mice and oxygen induced retinopathy (OIR) mice, used as models of RP and retinopathy of prematurity, respectively [ 9 , 10 ], show a positive response to BAR blockers acting mainly at BAR1 and BAR2 [ 11 , 12 , 13 , 14 ]. In particular, in the rd10 model, the BAR1/2 blocker metipranolol efficiently counteracts cone degeneration by reducing nitrosative damage to cones [ 11 ], while, in the OIR model, the BAR1/2 blocker propranolol prevents retinal neovascularization and dysfunction by reducing angiogenic processes [ 12 , 13 , 14 ].…”

“…In particular, the developmental expression of BAR2 was studied in concomitance with that of the main desensitization markers GRK2 and β-arrestin 2 in order to correlate BAR2 levels and their regulatory mechanisms with major events leading to cone death. Although the efficacy of metipranolol on nitrosative damage to cones has been previously reported [ 11 ], no information is available on whether BAR blockade affects the BAR system. Here, the effects of BAR blockade on BAR2, GRK2 and β-arrestin 2 are also determined in order to evaluate whether blocking BAR2 might affect desensitization processes.…”

Nitrosative Stress in Retinal Pathologies: Review

“…Metipranolol, an antiglaucoma and antihypertensive drug, slowed the rod and cone cell death in the rd10 model of RP [60]. This effect may be mediated by its ability to inhibit nitrosative stress [59].…”