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K. C. Nishihara, A. Oyejide, S. Matsumoto, D. H. Reser, B. S. Short, A. Wiese; The Relationship Between Full Field Electroretinography (ERG) and Retinal Histopathology in Rabbits After Intravitreal Injection of Glutamate Analogs. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2205.
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To evaluate the relationship between retinal function as measured by full-field electroretinography (ERG) and histopathology in rabbits after intravitreal injection of glutamate analogs with known effects on retinal toxicity.
Adult female New Zealand White rabbits (2/treatment group) received 140, 275, or 1385 µg/eye cis-2,3-piperidinedicarboxylic acid (PDA), or 1385 µg/eye PDA plus 293 µg/eye 2-amino, 4-phosphonobutryic acid (APB) by intravitreal injection (50µL). Control rabbits were given a sham and/or saline injection. The right eye was untreated. Rabbits were anesthetized, given an intravitreal injection of test article, and dark adapted for 30 minutes. ERG was carried out prior to injection, and 1.5 hr, 7 days, and 14 days post-injection. The following ERG stimuli were used: low and high intensity flash for dark-adapted (scotopic) eyes, and high intensity flash or 30 Hz flicker for light-adapted (photopic) eyes. At Day 14 post-injection, ocular tissues were obtained for microscopic evaluation.
Intravitreal injection of PDA alone led to decreases (30-68%) in ERG a- and/or b-wave amplitudes and implicit times (IT) at 1.5 hr post-injection (Day 1) under both scotopic and photopic conditions. These changes were reversible by Day 7 or 14 and did not correspond to any microscopic structural alterations except at 1385µg/eye PDA where minimal retinal degeneration localized to the central retina was observed in 1 of 2 rabbits. The combination of PDA/APB led to a 70-100% decrease in a- and/or b-wave amplitudes and IT at 1.5 hr post-injection that was sustained through Day 14. In addition, moderate diffuse retinal atrophy and necrosis, characterized by near complete loss of the ganglion cell and inner nuclear layers, along with disruption of the photoreceptor layer and the retinal pigment epithelium was observed microscopically at Day 14 after administering the combination of PDA/APB.
Following intravitreal injection of glutamate analogs in rabbits, ERG was capable of detecting transient changes in retinal function that were not manifested in retinal structure changes at 14 days after dosing, as well as immediate, severe and persistent changes in retinal function accompanied by retinal atrophy and necrosis at 14 days after dosing.
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