The study of the intracellular mechanism and its modulatory factor in the ischemic retina

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Our in vitro study demonstrated in the cultured retinal neurons that nitric oxide (NO) has dual actions in the NMDA-receptor mediated neurotoxcicity. That is, low concentration of NO protected retinal neurons by inhibiting the NMDA-channel activity but overproduction of NO,interacting with oxygenradicals lead to the death of retinal neurons in NMDA neuroxicity. We further evaluated how this findings were involved in the in vivo retinal ischemia. Based on our in vivo microdialysis study of the cat ratina, large release of glutamate occurred during ischemia and more prominently during reperfusion. Administration of MK-801 or L-NAME,aNO synthase (NOS) inhibitor, into the rat significantly inhibited the ischemia/reperfusioninduced reduction in the cell number of the ganglion cell layr and the thickness of the inner plexiform layr. Intravitreal injection of L-NAME inhibited NMDA-induced neurotoxicity in the retinal. Non-selective NOS inhibitor such as L-NAME inhibits not only neuronal NOS (nNOS) from neurotoxic action but also endothelial NOS (eNOS) from vasodilating action. Therefore, our findings that L-NAME also inhibited NMDA-induced neurotoxicity, indicate a principal role of NO-induced neurotoxicity in the pathogenesis of retinal ischemic injury albeit NO's potential ameliorating action as a vasodilator. It is thus concluded that NO generated through NMDA-receptors play a key role in the ischemia-induced damage in the inner layrs of the retina. According to our molecular genenic study, TUNEL positive cells were found in the inner retina after transient retinal ischemia. Furthermore, typical latter pattern after agarose gel electrophoresis of DNA was obtained from the ischemic retina, indicating the presence of internucleosomal DNA fragmentation. Thus, it is suggested that transient retinal ischemia induces apoptosis of the inner retinal neurons.