Oral Ursodeoxycholic Acid Crosses the Blood Retinal Barrier in Patients with Retinal Detachment and Protects Against Retinal Degeneration in an Ex Vivo Model

Abstract

Rhegmatogenous retinal detachment (RD) is a threatening visual condition and a human disease model for retinal degenerations. Despite successful reattachment surgery, vision does not fully recover, due to subretinal fluid accumulation and subsequent photoreceptor cell death, through mechanisms that recapitulate those of retinal degenerative diseases. Hydrophilic bile acids are neuroprotective in animal models, but whether they can be used orally for retinal diseases is unknown. Ursodeoxycholic acid (UDCA) being approved for clinical use (e.g., in cholestasis), we have evaluated the ocular bioavailability of oral UDCA, administered to patients before RD surgery. The level of UDCA in ocular media correlated with the extent of blood retinal barrier disruption, evaluated by the extent of detachment and the albumin concentration in subretinal fluid. UDCA, at levels measured in ocular media, protected photoreceptors from apoptosis and necrosis in rat retinal explants, an ex vivo model of RD. The subretinal fluid from UDCA-treated patients, collected during surgery, significantly protected rat retinal explants from cell death, when compared to subretinal fluid from control patients. Pan-transcriptomic analysis of the retina showed that UDCA upregulated anti-apoptotic, anti-oxidant, and anti-inflammatory genes. Oral UDCA is a potential neuroprotective adjuvant therapy in RD and other retinal degenerative diseases and should be further evaluated in a clinical trial.

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

“…Recently, metformin was found to potentially reduce the incidence of AMD in large, retrospective studies [51] that need to be interpreted with caution [52]. Taking into account the fact that no treatment is currently available to prevent or delay retinal degeneration, the effects of old and known drugs with a known safety profile could be evaluated in treated patients that are affected by retinal diseases that induce rapid retinal cell death, such as retinal detachment [53].…”

Bile Acid Signaling in Inflammatory Bowel Disease

“…Ursodeoxycholic acid (UDCA) is approved for clinical use in treatment of, e.g., primary sclerosing cholangitis [35]. It is under clinical trials in other indications such as liver diseases or for administration to patients before a retinal disattachment surgery [54]. The mechanisms of action are not well defined, but it is believed that UDCA acts as an anti-inflammatory, cytoprotective, and anti-apoptotic signaling molecule [55].…”

Comparative Analysis of Urso- and Tauroursodeoxycholic Acid Neuroprotective Effects on Retinal Degeneration Models

“…The main function of BA is the emulsification, absorption, and digestion of lipids. However, the hydrophilic secondary BAs, ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), the taurine conjugate of UDCA, that are also circulating at low levels, have also shown interesting neuroprotective effects in various neurodegenerative [ 1 ] and retinal disease [ 2 , 3 ]. Although antiapoptotic, anti-inflammatory, and antioxidant effects have been demonstrated for these molecules, little is known about primary signaling pathways through which bile acids act as neuroprotectants [ 4 , 5 , 6 ], and whether both molecules regulate similar pathways is unknown.…”

“…UDCA is approved by regulatory agencies for the treatment of gallstones. The ocular bioavailability of commercially available oral UDCA was recently evaluated after being administered to patients before retinal detachment surgery [ 3 ]. In ocular media, the levels of UDCA correlated with the extent of blood–retinal barrier disruption and reached neuroprotective levels.…”