title: Phloroglucinol protects retinal pigment epithelium and photoreceptor against all-trans-retinal-induced toxicity and inhibits A2E formation.
abstract: Among retinal macular diseases, the juvenile recessive Stargardt disease and the age-related degenerative disease arise from carbonyl and oxidative stresses (COS). Both stresses originate from an accumulation of all-trans-retinal (atRAL) and are involved in bisretinoid formation by condensation of atRAL with phosphatidylethanolamine (carbonyl stress) in the photoreceptor and its transformation into lipofuscin bisretinoids (oxidative stress) in the retinal pigment epithelium (RPE). As atRAL and bisretinoid accumulation contribute to RPE and photoreceptor cell death, our goal is to select powerful chemical inhibitors of COS. Here, we describe that phloroglucinol, a natural phenolic compound having anti-COS properties, protects both rat RPE and mouse photoreceptor primary cultures from atRAL-induced cell death and reduces hydrogen peroxide (H2 O2 )-induced damage in RPE in a dose-dependent manner. Mechanistic analyses demonstrate that the protective effect encompasses decrease in atRAL-induced intracellular reactive oxygen species and free atRAL levels. Moreover, we show that phloroglucinol reacts with atRAL to form a chromene adduct which prevents bisretinoid A2E synthesis in vitro. Taken together, these data show that the protective effect of phloroglucinol correlates with its ability to trap atRAL and to prevent its further transformation into deleterious bisretinoids. Phloroglucinol might be a good basis to develop efficient therapeutic derivatives in the treatment of retinal macular diseases.
authors.affiliation: Laboratoire de Biophysique Neurosensorielle, UMR INSERM 1107 Facultés de Médecine et de Pharmacie, Clermont-Ferrand, France.
authors.forename: David
authors.initials: D
authors.lastname: Cia
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cubizolle
authors.affiliation: Université Montpellier, Montpellier, France.|Institut des Biomolecules Max Mousseron (IBMM), UMR5247-CNRS-UM ENSCM Faculté de Pharmacie, Montpellier, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Crauste
authors.affiliation: Laboratoire de Biophysique Neurosensorielle, UMR INSERM 1107 Facultés de Médecine et de Pharmacie, Clermont-Ferrand, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacquemot
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guillou
authors.affiliation: Université Montpellier, Montpellier, France.|Institut des Biomolecules Max Mousseron (IBMM), UMR5247-CNRS-UM ENSCM Faculté de Pharmacie, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Vigor
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Angebault
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Montpellier, France.|Université Montpellier, Montpellier, France.|Centre de référence des affections sensorielles génétiques, CHRU, Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: Université Montpellier, Montpellier, France.|Institut des Biomolecules Max Mousseron (IBMM), UMR5247-CNRS-UM ENSCM Faculté de Pharmacie, Montpellier, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vercauteren
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Montpellier, France.|Université Montpellier, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Brabet
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019610:Cytoprotection / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000633:toxicity; D018384:Oxidative Stress; D010696:Phloroglucinol / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D020318:Rats, Long-Evans; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012172:Retinaldehyde / Q000633:toxicity*; D012176:Retinoids / Q000378:metabolism*
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); D001578:Benzopyrans; D020011:Protective Agents; D012176:Retinoids; D006861:Hydrogen Peroxide; D010696:Phloroglucinol; D012172:Retinaldehyde
keywords: all-trans-retinal; bisretinoid A2E; chromene adduct; phloroglucinol; photoreceptor; retinal pigment epithelium