title: Retinal function and morphology in rabbit after intravitreal injection of VEGF inhibitors.
abstract: OBJECTIVE
  To explore changes in morphology and function in the rabbit retina after intravitreal high-dose injection of three commonly used VEGF inhibitors.
  
  
  METHODS
  Forty-eight rabbits of mixed strain (6 months of age, body weight ≈ 3 kg) were randomized into four groups (n = 12). They were examined with full-field electroretinography (ERG) and with multifocal electroretinography (mf ERG) prior to drug exposure. The rabbits were then injected intravitreally with bevacizumab, ranibizumab, pegaptanib, or with a balanced saline solution. The dose of VEGF inhibitor was chosen to achieve a vitreous concentration approximately three times higher than the one clinically used in the adult human eye. ERG was then performed 8 weeks postinjection, and mf ERG 9 weeks postinjection. After 9 weeks, the rabbits were sacrificed and the sectioned retina was studied. Immunohistochemical analysis was performed of rods, cones, rod bipolar cells, horizontal cells, and amacrine cells.
  
  
  RESULTS
  Rabbits injected with VEGF inhibitors all showed significantly lower amplitude of the dark-adapted b-wave rod-mediated response to dim light, compared to the rabbits injected with BSS. The a wave (reflecting photoreceptor function) in the response to single flash white light was however not affected. Immunohistochemistry revealed a significant reduction in PKC labeling of rod bipolar cells in pegaptanib and ranibizumab injected eyes whereas bevacizumab injected eyes displayed normal PKC labeling. No apparent morphological change was seen with markers for remaining retinal cells.
  
  
  CONCLUSIONS
  Our results indicate that the use of high-dose intravitreal VEGF inhibitors in the rabbit eye affects rod-mediated retinal function and PKC expression in rod bipolars cells for at least 9 weeks after drug administration. The three VEGF inhibitors influence the retina slightly differently. These results are important for the understanding of drug action and when devising therapeutical strategies in new areas such as retinopathy of prematurity where vitreous volume is significantly lower compared to the adult eye.
authors.affiliation: Department of Ophthalmology, Lund University, Lund, Sweden.
authors.forename: Anna Cardiakidis
authors.initials: AC
authors.lastname: Myers
authors.forename: Monica
authors.initials: M
authors.lastname: Lövestam Adrian
authors.forename: Anitha
authors.initials: A
authors.lastname: Bruun
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ghosh
authors.forename: Sten
authors.initials: S
authors.lastname: Andréasson
authors.forename: Vesna
authors.initials: V
authors.lastname: Ponjavic
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage*; D000068258:Bevacizumab; D004195:Disease Models, Animal; D004596:Electroretinography; D007150:Immunohistochemistry; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011817:Rabbits; D000069579:Ranibizumab; D012160:Retina / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib; D000068258:Bevacizumab; D000069579:Ranibizumab