title: Synthesis of docosahexaenoic acid from eicosapentaenoic acid in retina neurons protects photoreceptors from oxidative stress.
abstract: Oxidative stress is involved in activating photoreceptor death in several retinal degenerations. Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, protects cultured retina photoreceptors from apoptosis induced by oxidative stress and promotes photoreceptor differentiation. Here, we investigated whether eicosapentaenoic acid (EPA), a metabolic precursor to DHA, had similar effects and whether retinal neurons could metabolize EPA to DHA. Adding EPA to rat retina neuronal cultures increased opsin expression and protected photoreceptors from apoptosis induced by the oxidants paraquat and hydrogen peroxide (H2 O2 ). Palmitic, oleic, and arachidonic acids had no protective effect, showing the specificity for DHA. We found that EPA supplementation significantly increased DHA percentage in retinal neurons, but not EPA percentage. Photoreceptors and glial cells expressed Δ6 desaturase (FADS2), which introduces the last double bond in DHA biosynthetic pathway. Pre-treatment of neuronal cultures with CP-24879 hydrochloride, a Δ5/Δ6 desaturase inhibitor, prevented EPA-induced increase in DHA percentage and completely blocked EPA protection and its effect on photoreceptor differentiation. These results suggest that EPA promoted photoreceptor differentiation and rescued photoreceptors from oxidative stress-induced apoptosis through its elongation and desaturation to DHA. Our data show, for the first time, that isolated retinal neurons can synthesize DHA in culture. Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in retina photoreceptors, and its precursor, eicosapentaenoic acid (EPA) have multiple beneficial effects. Here, we show that retina neurons in vitro express the desaturase FADS2 and can synthesize DHA from EPA. Moreover, addition of EPA to these cultures protects photoreceptors from oxidative stress and promotes their differentiation through its metabolization to DHA.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Department of Biology, Biochemistry and Pharmacy, Univ Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Simón
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Department of Biology, Biochemistry and Pharmacy, Univ Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Daniela L
authors.initials: DL
authors.lastname: Agnolazza
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Department of Biology, Biochemistry and Pharmacy, Univ Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Olga Lorena
authors.initials: OL
authors.lastname: German
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Department of Biology, Biochemistry and Pharmacy, Univ Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Garelli
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Department of Biology, Biochemistry and Pharmacy, Univ Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Politi
authors.affiliation: Cell Biology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, USA.|Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, USA.
authors.forename: Martin-Paul
authors.initials: MP
authors.lastname: Agbaga
authors.affiliation: Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, USA.|Ophthalmology/Cell Biology, Univ of Oklahoma Hlth Sci Ctr, Oklahoma City, Oklahoma, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Anderson
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Department of Biology, Biochemistry and Pharmacy, Univ Nacional del Sur (UNS)-CONICET, Bahía Blanca, Buenos Aires, Argentina.
authors.forename: Nora P
authors.initials: NP
authors.lastname: Rotstein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010269:Paraquat / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020011:Protective Agents; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D010269:Paraquat
keywords: apoptosis; differentiation; fatty acid desaturase; omega-3 fatty acids; polyunsaturated fatty acid; retina