title: Systemic treatment with a 5HT1a agonist induces anti-oxidant protection and preserves the retina from mitochondrial oxidative stress.
abstract: Chronic oxidative stress contributes to age related diseases including age related macular degeneration (AMD). Earlier work showed that the 5-hydroxy-tryptamine 1a (5HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) protects retinal pigment epithelium (RPE) cells from hydrogen peroxide treatment and mouse retinas from oxidative insults including light injury. In our current experiments, RPE derived cells subjected to mitochondrial oxidative stress were protected from cell death by the up-regulation of anti-oxidant enzymes and of the metal ion chaperone metallothionein. Differentiated RPE cells were resistant to oxidative stress, and the expression of genes for protective proteins was highly increased by oxidative stress plus drug treatment. In mice treated with 8-OH-DPAT, the same genes (MT1, HO1, NqO1, Cat, Sod1) were induced in the neural retina, but the drug did not affect the expression of Sod2, the gene for manganese superoxide dismutase. We used a mouse strain deleted for Sod2 in the RPE to accelerate age-related oxidative stress in the retina and to test the impact of 8-OH-DPAT on the photoreceptor and RPE degeneration developed in these mice. Treatment of mice with daily injections of the drug led to increased electroretinogram (ERG) amplitudes in dark-adapted mice and to a slight improvement in visual acuity. Most strikingly, in mice treated with a high dose of the drug (5 mg/kg) the structure of the RPE and Bruch's membrane and the normal architecture of photoreceptor outer segments were preserved. These results suggest that systemic treatment with this class of drugs may be useful in preventing geographic atrophy, the advanced form of dry AMD, which is characterized by RPE degeneration.
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Manas R
authors: MR
authors: Biswal
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Chulbul M
authors: CM
authors: Ahmed
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Cristhian J
authors: CJ
authors: Ildefonso
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Pingyang
authors: P
authors: Han
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Hong
authors: H
authors: Li
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Hiral
authors: H
authors: Jivanji
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA.
authors: Haoyu
authors: H
authors: Mao
authors: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Box 100266, Gainesville, FL, 32610-0266, USA. Electronic address: lewin@ufl.edu.
authors: Alfred S
authors: AS
authors: Lewin
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000187:drug effects; D000099156:Superoxide Dismutase 2
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D008668:Metallothionein; D010088:Oxidoreductases; D017382:Reactive Oxygen Species; D044282:Receptor, Serotonin, 5-HT1A; D017366:Serotonin Receptor Agonists; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: 5-hydroxy-tryptamine 1a receptor; Age related macular degeneration; Drug therapy; Mitochondria; Mouse model; Oxidative stress; Retinal pigment epithelium; Superoxide dismutase