title: The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium.
abstract: Age-related macular degeneration (AMD), a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT(1A) receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS)-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE) cells in the presence or absence of the 5-HT(1A) receptor agonist, 8-OH DPAT. 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagy- and POS-derived lipofuscin compared to control. Reduction in autophagy-induced lipofuscin was sustained for 4 weeks following removal of the drug. The ability of 8-OH DPAT to reduce oxidative damage following exposure to 200 µM H(2)O(2) was assessed. 8-OH DPAT reduced superoxide generation and increased mitochondrial superoxide dismutase (MnSOD) levels and the ratio of reduced glutathione to the oxidized form of glutathione in H(2)O(2)-treated cells compared to controls and protected against H(2)O(2)-initiated lipid peroxidation, nitrotyrosine levels and mitochondrial damage. SOD2 knockdown mice, which have an AMD-like phenotype, received daily subcutaneous injections of either saline, 0.5 or 5.0 mg/kg 8-OH DPAT and were evaluated at monthly intervals. Systemic administration of 8-OH DPAT improved the electroretinogram response in SOD2 knockdown eyes of mice compared to knockdown eyes receiving vehicle control. There was a significant increase in the ONL thickness in mice treated with 8-OH DPAT at 4 months past the time of MnSOD knockdown compared to untreated controls together with a 60% reduction in RPE lipofuscin. The data indicate that 5-HT(1A) agonists can reduce lipofuscin accumulation and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT(1A) receptor agonists may have potential as therapeutic agents in the treatment of retinal degenerative disease.
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Prajitha
authors.initials: P
authors.lastname: Thampi
authors.forename: Haripriya Vittal
authors.initials: HV
authors.lastname: Rao
authors.forename: Sayak K
authors.initials: SK
authors.lastname: Mitter
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
authors.forename: Haoyu
authors.initials: H
authors.lastname: Mao
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Soojung
authors.initials: S
authors.lastname: Seo
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.forename: Alfred S
authors.initials: AS
authors.lastname: Lewin
authors.forename: Carl
authors.initials: C
authors.lastname: Romano
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014785:Vision, Ocular / Q000187:drug effects / Q000502:physiology
chemical_list: D000975:Antioxidants; D008062:Lipofuscin; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C078730:serotonin 5 receptor; D013481:Superoxides; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin