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

• Published in: Neurotherapeutics 2021-04, Vol.18 (2), p.1325-1338
• Main Authors: Daruich, Alejandra, Jaworski, Thara, Henry, Hugues, Zola, Marta, Youale, Jenny, Parenti, Léa, Naud, Marie-Christine, Delaunay, Kimberley, Bertrand, Mathilde, Berdugo, Marianne, Kowalczuk, Laura, Boatright, Jeffrey, Picard, Emilie, Behar-Cohen, Francine
• Format: Article
• Language: English
• Subjects: Administration, Oral; Albumins - metabolism; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Bile acids; Bioavailability; Biological Availability; Biomedical and Life Sciences; Biomedicine; Blood-Retinal Barrier - metabolism; Cell death; Cell Line; Cholagogues and Choleretics - metabolism; Cholagogues and Choleretics - pharmacology; Cholestasis; Cryosurgery; Degenerative diseases; Explants; Female; Humans; In Vitro Techniques; Inflammation; Laser Therapy; Life Sciences; Male; Middle Aged; Necrosis; Neurobiology; Neurology; Neuroprotection; Neurosciences; Neurosurgery; Original; Original Article; Oxidants; Patients; Photoreceptor Cells, Vertebrate - drug effects; Photoreceptor Cells, Vertebrate - pathology; Photoreceptors; Rats; Retina; Retina - drug effects; Retina - pathology; Retina - surgery; Retinal Cone Photoreceptor Cells - drug effects; Retinal Cone Photoreceptor Cells - pathology; Retinal degeneration; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Degeneration - therapy; Retinal detachment; Retinal Detachment - metabolism; Retinal Detachment - pathology; Retinal Detachment - therapy; Subretinal Fluid - chemistry; Surgery; Ursodeoxycholic acid; Ursodeoxycholic Acid - metabolism; Ursodeoxycholic Acid - pharmacology; Vitrectomy
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-021-01009-6

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.