Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes

Abstract

Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials.

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

“…There are indications that ET activity may be involved in DR, and evidence has been provided that ET inhibition may ameliorate the pathologic signs of DR. Indeed, an ETRA antagonist has been reported to block the diabetes-induced upregulation of both VEGF and ICAM-1 in retinas of STZ rats (Masuzawa et al, 2006), while other observations have described positive effects of ETR inhibition on both neuronal and vascular changes seen in DR. For instance, ETRA and/or ETRB inhibitors reduced retinal thinning, the number of apoptotic cells, and the levels of the pro-inflammatory cytokine TNFα in diabetic rat retinas, and at the same time they also reduced pericyte loss, capillary degeneration, vascular leakage, and the levels of both VEGF and ICAM-1 (Chou et al, 2014; Alrashdi et al, 2018; Bogdanov et al, 2018).…”

Effect of Topical Administration of Somatostatin on Retinal Inflammation and Neurodegeneration in an Experimental Model of Diabetes

“…In terms of clinical translation, it should be noted that these results cannot be completely extrapolated to human beings. Indeed, in our experience, the db/db mouse model is very sensitive to both neuroprotective and anti-inflammatory agents [ 20 , 46 , 47 , 48 ], which could not be the case in humans. Another point to be considered is whether the dose of SST used in our in vitro experiments reflects what occurs in physiological conditions.…”

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

“…Substances that alter the RAS have been extensively studied, with exciting new prospects [ 147 – 149 ]. Other promising agents with neuroprotective effects in animal models of DRN include GLP-1RA liraglutide [ 150 – 154 ], lamivudine (P2rx7 inhibitor) [ 155 ], endothelin-1 receptor antagonists [ 156 , 157 ], and agents lowering intraocular pressure [ 158 , 159 ].…”

“…Topical administration of bosentan (a dual endothelin receptor antagonist) in diabetic (db/db) mice was shown to result in a significant decrease of reactive gliosis and apoptosis. Anti-inflammatory, as well as anti-VEGF mechanisms, was implicated in bosentan's auspicious effects [ 157 ].…”