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S. Zayit- Soudry, E. Zemel, A. Loewenstein, I. Perlman; The Importance of VEGF for Normal Function of the Rabbit Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5375.
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Vacular Endothelial Growth Factor (VEGF) is known to be a survival factor for endothelial cells, as well as a mitogen for RPE cells. It has also been suggested to display important neuroprotective activity. Therefore, frequent administration of Bevacizumab or Ranibizumab, as currently practiced in the treatment of neovascular AMD, may ameliorate macular function, but may simultaneously inhibit the beneficial action of VEGF, thus causing loss of function of the normal peripheral retina. We aimed to determine whether long-term VEGF suppression has undesirable effects on rabbit retinal function.
Adult albino rabbits underwent repeat intravitreal injections of Bevacizumab or Ranibizumab (Genentech, USA). In each rabbit, the right eye was injected according to the study protocol, while the left eye was injected with a similar volume of sterile saline solution and thus served as control.Repeat electrophysiologic assessment, including ERG and VEP was performed every 2 weeks. Dark-adapted as well as light-adapted responses were recorded simultaneously from experimental and control eyes. For each rabbit, the b-waves of both eyes were plotted as a function of log flash intensity, and the curve was fitted to a Michaelis-Menten type function in order to derive Vmax, the maximum response amplitude, andσ, the semi-saturation constant. The ratio between Vmax values of both eyes was used to assess retinal function. After 9 injections the rabbits were sacrificed, and the retinas were prepared for histopathological and immunocytochemistry studies.
The ERG studies demonstrated practically no functional damage in rabbits injected with repeat dosing of Bevacizumab or Ranibizumab. Mean Vmax and σ values calculated at each time point indicated a similar retinal function of experimental and control eyes. Furthermore, no histopathological damage could be observed in the retinas of rabbits injected with repeat dosing of anti-VEGF antibodies.
The electroretinographic and histologic data presented in our study show that long term VEGF suppression, administered as repeat intravitreal anti-VEGF dosing, has no deleterious effect on the functional integrity of the rabbit retina. Ranibizumab and Bevacizumab have a lower affinity for rabbit VEGF in comparison with human VEGF, therefore it is possible that repeat intravitreal injections of these antibodies yielded incomplete VEGF inhibition in rabbits. Further studies are required to verify whether long-term VEGF suppression has a deleterious effect on retinal function in humans.
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