Ultrastructural and biochemical studies on the neuroprotective effects of excitatory amino acid antagonists in the ischemic rat retina.

Abstract

The effects of glutamate receptor agonists were evaluated, by utilizing the electron microscope, in a photothrombotic occlusion model of rat retinal vessels in order to study the ischemic damage and its antagonism in each morphologically identified population of retinal neurons. Rats were systemically injected with rose bengal fluorescein dye and one of their eyes was then exposed to bright light. This treatment caused neuronal damage and reduced the activities of the neuronal marker enzymes, choline acetyltransferase and glutamate decarboxylase, by approximately 75%. A single intravitreal injection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinoxaline (NBQX, 10-50 nmol), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, or of thiokynurenate (100-400 nmol), which also antagonizes N-methyl-D-aspartate (NMDA) receptors, performed immediately after the lesion, significantly reduced this loss. The electron microscope examination showed major damage in each type of retinal neuron, the pigment epithelium, and the microvessels. NBQX or thiokynurenic acid reduced, in a comparable manner, the effects of ischemia on the pigment epithelium, the photoreceptors, and the bipolar and the horizontal cells. NBQX was particularly efficient in reducing the damage to the amacrine cells located in the inner nuclear layer. The displaced amacrine and ganglion cells were not protected by NBQX but were almost completely spared in animals treated with thiokynurenate. These results show that antagonism of AMPA receptors is sufficient to reduce ischemic damage in a large number of retinal neurons, but that neuroprotection in the ganglion cell layer may be obtained only with agents which also antagonize NMDA receptors.