ULTRASTRUCTURAL AND BIOCHEMICAL-STUDIES ON THE NEUROPROTECTIVE EFFECTS OF EXCITATORY AMINO-ACID ANTAGONISTS IN THE ISCHEMIC RAT RETINA

The effects of glutamate receptor agonists were evaluated, by utilizin g the electron microscope, in a photo-thrombotic occlusion model of ra t retinal vessels in order to study the ischemic damage and its antago nism 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 cau sed neuronal damage and reduced the activities of the neuronal marker enzymes, choline acetyltransferase and glutamate decarboxylase, by app roximately 75%. A single intravitreal injection of 2,3-dihydroxy-6-nit ro-7-sulfamoylbenzoquinoxaline (NBQX, 10-50 nmol), an antagonist of al pha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) recepto rs, or of thiokynurenate (100-400 nmol), which also antagonizes N-meth yl-D-aspartate (NMDA) receptors, performed immediately after the lesio n, significantly reduced this loss. The electron microscope examinatio n showed major damage in each type of retinal neuron, the pigment epit helium, 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 wa s particularly efficient in reducing the damage to the amacrine cells located in the inner nuclear layer. The displaced amacrine and ganglio n cells were not protected by NBQX but were almost completely spared i n animals treated with thiokynurenate. These results show that antagon ism of AMPA receptors is sufficient to reduce ischemic damage in a lar ge number of retinal neurons, but that neuroprotection in the ganglion cell layer may be obtained only with agents which also antagonize NMD A receptors. (C) 1997 Academic Press.