Glutamate receptor antagonists protect against ischemia-induced retinal damage

Abstract

The effects of intravitreal injections of excitatory amino acid receptor antagonists have been studied on the ischemic neuronal damage induced by photochemical occlusion of the retinal vessels. Rats were systemically injected with rose bengal fluorescein dye and one of their eyes was exposed to bright light. The activities of the enzymes, choline-acetyltransferase and glutamate decarboxylase, were measured as an index of neuronal loss in the lesioned tissue. Lesioned retinas had a 75 ± 5% reduction in choline-acetyltransferase activity and a 72 ± 8% reduction in glutamate-decarboxylase activity, suggesting that the lesion causes a massive loss of retinal neurons, which use acetylcholine or γ-aminobutyric acid (GABA) as neurotransmitter. A single intravitreal injection of excitatory amino acid receptor antagonists, performed immediately after the lesion, significantly reduced this loss. Both α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N- methyl- D- aspartate ) (NMDA) types of ionotropic glutamate receptor antagonists were active in a dose-dependent manner. Almost complete protection was also obtained with relatively large doses of thiokynurenic acid (400 nmol), a non-selective antagonist of both AMPA and NMDA glutamate receptors, while 7-Cl-thiokynurenic acid, a potent and selective glycine receptor antagonist, was not active up to 200 nmol. These results strongly suggest that excitotoxic mechanisms are involved in ischemia-induced neuronal death in the retina and that appropriate treatments with antagonists of both AMPA and NMDA receptor types may significantly reduce this damage.