title: A novel in vivo model of focal light emitting diode-induced cone-photoreceptor phototoxicity: neuroprotection afforded by brimonidine, BDNF, PEDF or bFGF.
abstract: We have investigated the effects of light-emitting diode (LED)-induced phototoxicity (LIP) on cone-photoreceptors and their protection with brimonidine (BMD), brain-derived neurotrophic factor (BDNF), pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF) or basic fibroblast growth factor (bFGF). In anesthetized, dark adapted, adult albino rats a blue (400 nm) LED was placed perpendicular to the cornea (10 sec, 200 lux) and the effects were investigated using Spectral Domain Optical Coherence Tomography (SD-OCT) and/or analysing the retina in oriented cross-sections or wholemounts immune-labelled for L- and S-opsin and counterstained with the nuclear stain DAPI. The effects of topical BMD (1%) or, intravitreally injected BDNF (5 µg), PEDF (2 µg), CNTF (0.4 µg) or bFGF (1 µg) after LIP were examined on wholemounts at 7 days. SD-OCT showed damage in a circular region of the superotemporal retina, whose diameter varied from 1,842.4±84.5 µm (at 24 hours) to 1,407.7±52.8 µm (at 7 days). This region had a progressive thickness diminution from 183.4±5 µm (at 12 h) to 114.6±6 µm (at 7 d). Oriented cross-sections showed within the light-damaged region of the retina massive loss of rods and cone-photoreceptors. Wholemounts documented a circular region containing lower numbers of L- and S-cones. Within a circular area (1 mm or 1.3 mm radius, respectively) in the left and in its corresponding region of the contralateral-fellow-retina, total L- or S-cones were 7,118±842 or 661±125 for the LED exposed retinas (n = 7) and 14,040±1,860 or 2,255±193 for the fellow retinas (n = 7), respectively. BMD, BDNF, PEDF and bFGF but not CNTF showed significant neuroprotective effects on L- or S-cones. We conclude that LIP results in rod and cone-photoreceptor loss, and is a reliable, quantifiable model to study cone-photoreceptor degeneration. Intravitreal BDNF, PEDF or bFGF, or topical BMD afford significant cone neuroprotection in this model.
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Ortín-Martínez
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Valiente-Soriano
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: García-Ayuso
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alarcón-Martínez
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Jiménez-López
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Bernal-Garro
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Nieto-López
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Francisco Manuel
authors.initials: FM
authors.lastname: Nadal-Nicolás
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: María Paz
authors.initials: MP
authors.lastname: Villegas-Pérez
authors.affiliation: Zeteo Drug Discovery LLC, Irvine, California, United States of America.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Wheeler
authors.affiliation: Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vidal-Sanz
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D000068438:Brimonidine Tartrate; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D004581:Electronics; D005136:Eye Proteins / Q000494:pharmacology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D008027:Light / Q000009:adverse effects*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects*; D015843:Serpins / Q000494:pharmacology*; D013997:Time Factors; D041623:Tomography, Optical Coherence; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000068438:Brimonidine Tartrate; D005136:Eye Proteins; D016222:Fibroblast Growth Factor 2; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011810:Quinoxalines; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor