DL-α-Aminoadipic acid

Purpose: Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (AAA) is a new animal model for retinal neovascularization (RNV) reported in rabbits. This study performs longitudinal multimodal imaging for up to 1 year to evaluate DL-AAA RNV in both New Zealand white (NZW) rabbits and Dutch-Belted pigmented (DBP) rabbits. Method: Detailed characterization and quantification of this model were performed in these two strains in 32 eyes by optical coherence tomography (OCT), fundus photography, and fluorescein angiography (FA) for up to 16 weeks following DL-AAA administration in 32 eyes and up to 52 weeks in 5 eyes. H & E histology was also performed in these two strains 8 weeks after injection of DL-AAA. Result: RNV was successfully generated using 50 μL 80 mM DL-AAA solution for DBP rabbits and 80 μL 80 mM DL-AAA for NZW rabbits. The incidence of persistent vascular leakage is 100% (15/15) for DBP rabbits and 70.6% (12/17) for NZW rabbits at 16 weeks. Complications with NZW rabbits ultimately decreased the efficiency in NZW rabbits to 58.8% (10/17) of NZW rabbits getting persistent (to 16 weeks) vascular leakage without ocular complications as compared with 100% (15/15) in DBP rabbits. Five eyes (2 DBP and 3 NZW) were selected from those demonstrating RNV at 16 weeks and were monitored for up to 52 weeks. All 5 demonstrated persistent RNV to 52 weeks. Quantification of the mean leakage area (MLA) in DBP rabbits is more accurate than in NZW rabbits since the reduced contrast between the leakage and background in NZW rabbits makes it more challenging to quantify. Conclusion: DL-AAA can induce persistent and quantifiable RNV in both DBP and NZW rabbits. DBP rabbits have a higher success rate, lower required volume of DL-AAA, and more accurate method for quantification that could be more desirable.

Purpose: Macular telangiectasia type 2 (MT2) is a condition of uncertain etiology characterized by retinal vascular abnormalities, depletion of luteal pigment, and photoreceptor loss. To model this condition, the authors recently used a purportedly glial-selective toxin, DL-α-aminoadipic acid (DL-α-AAA), to test the effect of Müller cell disruption on the blood-retinal barrier in rats. In this study, they investigated macular changes after subretinal injection of DL-α-AAA in monkeys. Methods: Various doses of DL-α-AAA were injected beneath the macula in eight monkey eyes. Eyes were examined by multifocal electroretinography (mfERG), optical coherence tomography (OCT), fundus autofluorescence, color photography, and fluorescein angiography. Five months after injection, eyes were examined by histology and immunohistochemistry for changes in photoreceptors and the retinal glia. In vitro studies evaluated the effect of DL-α-AAA on 661W cone photoreceptor viability. Results: Subretinal injection of DL-α-AAA resulted in virtually complete ablation of photoreceptors in the injected area, as shown by OCT and histology, and severely impaired mfERG responses. Müller cells, albeit activated, survived the injury. Macular pigment remained unchanged in the central fovea. Subretinal injection of DL-α-AAA did not induce vascular leakage, though it increased the fundus autofluorescence. DL-α-AAA had a dose-dependent toxic effect on 661W photoreceptors. Conclusions: Submacular injection of DL-α-AAA induced severe damage to photoreceptors but failed to eliminate Müller cells in monkeys. Central macular pigment persisted despite loss of photoreceptors, and the retinal vasculature was unaffected. These observations may have significance in studying the roles of different cellular components in the pathogenesis of MT2.

Aim: To investigate the effect of intravitreal injection of DL-alpha-aminoadipic acid (DL-α-AAA) on ocular refractive state and retinal dopamine, transforming growth factor-β2 (TGFβ2), vasoactive intestinal polypeptide (VIP) in guinea pig form-deprived myopia. Methods: Four-week-old pigmented guinea pigs were randomly assigned to 4 groups: normal control, deprivation, deprivation plus DL-α-AAA, deprivation plus saline. Form deprivation was induced with the self-made translucent eye shields, and lasted for 14 days. 8µg DL-α-AAA was injected into the vitreous chamber of deprived eyes. The corneal radius of curvature, refraction and axial length were measured. Retinal dopamine content was evaluated by the high-performance liquid chromatography with electrochemical detection, and TGFβ2 and VIP protein were detected by Western blotting. Results: Fourteen days of eye occlusion caused the axial length to elongate and become myopic in the form-deprived eyes, with the decrease of retinal dopamine and the increase of TGFβ2 and vasoactive intestinal polypeptide (VIP) protein. Intravitreal injection of DL-α-AAA could inhibit the myopic shift from (-3.65±1.06)D to (-1.48±0.63)D, P<0.01 due to goggles occluding and cause the decrease of retinal TGFβ2 protein in the deprived eyes. However, intravitreal injection of DL-α-AAA had no significant effect on retinal dopamine and VIP protein in deprived eyes. Retinal TGFβ2 protein correlated highly with the ocular refraction (y=-3.34+0.31/x, F=74.75, P<0.001) and axial length (y=8.39-0.02/x, F=48.32, P<0.001) in different treatment groups. Conclusion: Intravitreal injection of DL-α-AAA is effectively able to suppress the development of form deprivation myopia, which may be associated with retinal TGFβ2 protein in guinea pigs.