Abstract
Abstract: :
Purpose: Excitotoxic neuronal cell death following ischemia may involve cyclooxygenase-2 (COX-2) acting as a signaling pathway, which contributes to ischemic neuronal cell death. In brain ischemia, COX-2 induction occurs in response to glutamate excitotoxicity. N-methyl-D-aspartic acid (NMDA) receptors are widely distributed in the rat retina and neuronal cell death following ischemia is due, in part, to excitotoxicity. We, therefore, have determined whether excitotoxicity following retinal ischemia causes expression of COX-2 and whether products of COX-2 contribute to neuronal cell death. Methods: Retinal ischemia was induced by elevating IOP above systolic blood pressure for 75 min. Rats were pretreated with MK801, an NMDA receptor antagonist, or with SC-58236, an inhibitor of COX-2. Activation of microglia, breakdown of the blood-retinal barrier and PMN leukocyte invasion were determined. The survival of retinal ganglion cells was quantitated by retrograde labeling of Fluoro-Gold. COX-2 protein was determined by immunohistochemistry on wax sections and by immunoblot analysis. Results: In the normal rat retina, COX-2 was present in a few neurons in the inner nuclear layer and ganglion cell layer. At 6 hr after ischemia, COX-2 was significantly induced in the perinuclear region and the processes of Müller cells and in some neurons, such as horizontal cells and amacrine cells in the INL. Interestingly, a few cells that are likely to be retinal ganglion cells also induced COX-2. In MK801 treated animals, COX-2 expression was significantly decreased in neurons but not in Müller cells after ischemia. Furthermore, MK801 or SC-58236 markedly increased the survival of retinal ganglion cells after ischemia. After ischemia, the inhibitor of COX-2 blocked microglia activation, breakdown of the blood-retinal barrier and invasion of PMN leukocytes. Conclusions: COX-2 is differentially induced in neurons in the rat retina after ischemia by excitotoxic activation of NMDA receptors. Prostaglandins synthesized by COX-2 in neurons signal neurodegenerative events following retinal ischemia.
Keywords: retinal degenerations: cell biology • ischemia • excitatory neurotransmitters