We propose to investigate the hypothesis that ischemia-induced degeneration of neurons in the retina, a clinical condition frequently leading to blindness, is mediated by the endogenous excitatory amino acids (EAA), glutamate and aspartate. These compounds are major excitatory transmitters in the retina and also have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, recently, new classes of potent EAA antagonists have been discovered. Several lines of evidence suggest that endogenous EAA may cause or that EAA antagonists can prevent neuronal damage associated with anoxia/ischemia. However, evidence for in vivo protection against anoxic/ischemic brain damage is rather tenuous because of inadequacies inherent in the animal models available for such studies. The retina lends itself to both in vitro and in vivo studies of ischemic neuronal degeneration. We have developed an oxygen/glucose deprivation model for studying ischemic neuronal degeneration in the isolated (ex vivo) chick embryo retina and propose to screen various EAA antagonists (anti-excitotoxins) for their ability to prevent such degeneration in this model. We have developed a model for reproducibly inducing a similar pattern of acute neuronal degeneration in the in vivo adult rat retina by using a rose bengal dye/photothrombosis approach to occlude the retinal vasculature. We are now developing a model of delayed neuronal degeneration in the in vivo adult rat retina using an intraocular hypertension approach. We propose to continue developing the latter model, to utilize both rodent models to study mechanisms of ischemic retinal degeneration, and to systematically evaluate anti-excitotoxic drugs found effective in protecting the isolated chick retina against ischemic degeneration for their ability to protect against acute and delayed ischemic damage in the in vivo rat retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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Washington University
Schools of Medicine
Saint Louis
United States
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Young, Chainllie; Tenkova, Tatyana; Dikranian, Krikor et al. (2004) Excitotoxic versus apoptotic mechanisms of neuronal cell death in perinatal hypoxia/ischemia. Curr Mol Med 4:77-85
Izumi, Yukitoshi; Matsukawa, Mio; Benz, Ann M et al. (2004) Role of ammonia in reversal of glutamate-mediated Muller cell swelling in the rat retina. Glia 48:44-50
Tenkova, Tatyana; Young, Chainllie; Dikranian, Krikor et al. (2003) Ethanol-induced apoptosis in the developing visual system during synaptogenesis. Invest Ophthalmol Vis Sci 44:2809-17
Izumi, Yukitoshi; Hammerman, Seth B; Kirby, Charity O et al. (2003) Involvement of glutamate in ischemic neurodegeneration in isolated retina. Vis Neurosci 20:97-107
Olney, John W; Tenkova, Tatyana; Dikranian, Krikor et al. (2002) Ethanol-induced caspase-3 activation in the in vivo developing mouse brain. Neurobiol Dis 9:205-19
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Olney, John W (2002) New insights and new issues in developmental neurotoxicology. Neurotoxicology 23:659-68
Olney, John W; Tenkova, Tatyana; Dikranian, Krikor et al. (2002) Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res 133:115-26
Olney, John W; Wozniak, David F; Farber, Nuri B et al. (2002) The enigma of fetal alcohol neurotoxicity. Ann Med 34:109-19
Olney, John W; Wozniak, David F; Jevtovic-Todorovic, Vesna et al. (2002) Drug-induced apoptotic neurodegeneration in the developing brain. Brain Pathol 12:488-98

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