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Matthew S Lawrence, Jordan Attwood, Alex Lewis, Rohn Brookes, Vernard Woodley, Meghan Tucker, Wenzheng Hu, Robin J Goody, Sean Callanan, Demetrios Vavvas; Characterization and application of a nonhuman primate model of non-arteritic anterior ischemic optic neuropathy for therapeutic screening. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5544.
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To characterize the nature and time course of optic nerve and retinal pathology following induction of non-arteritic anterior ischemic optic neuropathy (NAION) by focal photothrombotic insult to the optic nerve head (ONH) in African green monkeys, and to evaluate the effect of candidate neuroprotective agents in reducing the elicited pathology.
Fifteen adult monkeys received unilateral ONH laser treatment (wavelength 532mm; power 100mW; spot size 500mm; duration 9 seconds x 4), immediately following intravenous administration of rose bengal (0.1 ml/kg of 25 mg/kg) to induce oxidative endothelial injury of ONH microvasculature. Eyes were evaluated by slit lamp exam, color fundus photography, fluorescence angiography, optical coherence tomography (OCT) and electroretinography (ERG) at baseline and days 1, 7, 14, 28, 56 and 84 post-laser. Apoptosis and necrosis inhibitors or vehicle were administered intravitreally immediately following laser treatment.
Photothrombotic injury to the ONH employing the applied laser parameters consistently triggered the onset and evolution of a pathology very similar to clinical NAION, with ONH edema within 24 hours, followed by retinal venous stasis, peripapillary hemorrhages, and optic nerve fiber layer (ONFL) thickening over the ensuing week, which gradually resolved, leaving residual ONH pallor and ONFL thinning. Electrophysiological changes were correlated with ONFL changes detectible by OCT. Terminal histology findings were additionally correlated with in-life exam findings. Intervention with pan-caspase and receptor interacting protein 1 kinase inhibitors at the doses explored positively modulated endpoints, although demonstration of statistically significant therapeutic effect was limited by sample size.
Photothrombotic NAION in the green monkey exhibits pathological changes very similar to the human condition with early onset ONH and retinal edema followed by ONFL thinning with associated ERG changes indicative of functional deficit, all of which can be evaluated in a quantitative, longitudinal manner. This supports application of the model as a test system to further understand the pathophysiology of NAION and the evaluation of candidate therapies, the utility of which as been demonstrated in our initial exploration of the therapeutic effect of cell death pathway inhibitors.
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