With an experimental pathology approach, this project seeks to probe the pathogenetic mechanisms of retinal degeneration initiated by light with three classes of compounds which possibly affect different pathogenetic pathways of retinal photic injury. Animal models of the retinal photic injury in rats and cynomolgus monkeys will be used. The degeneration initiated by light and modified by these compounds will be studied by morphologic, morphometric and biochemical techniques. Specifically, the retinal lesion will be examined (1) qualitatively by light and electron microscopy, (2) quantitatively by morphometric assessment of photoreceptor nuclei, pigment epithelial cells, subretinal macrophages, and rods and cone elements, and (3) biochemically by measurement of loss rhodopsin as an additional quantitative index of photoreceptor loss and recovery. The three classes of compounds are: (1) a calcium antagonist, flunarizine will be used to examine the role of calcium overload as one of the pathogenetic mechanisms of photoreceptor cell death. (2) corticosteroids including dexamethasone and methylprednisolone will be used to investigate the effect of anti-inflammatory/anti-lipid peroxidation agents on retinal photic injury. (3) polyamines including putrescine, spermidine, and spermine will be used to probe the effect of cellular growth/differentiation modulators on the disease process. For each class of compounds, we shall examine its effectiveness on amelioration of retinal photic injury and subsequently dose-response relationship. We shall further examine the distribution of these compounds in the retina in relationship to dose administered. Other mechanisms of actions of these compounds will be investigated by various experiments including determination of Ca++-Calmodulin binding in the retina after photic injury in an immunopathological study with or without calcium antagonists. The above drugs in different combination with antioxidents, which we have studies in the previous grant period will be administered to rats to evaluate possible additive effects. To explore possible clinical application, selective drugs will be administered to monkeys to evaluate their effect on retinal photic injuries in the primate retina. The long-term objective of this project is to examine compounds which would modify photoreceptor degeneration of the retina initiated by mild photic insult in order to develop new therapeutic measures for photoreceptor degeneration which, as yet, has no medical remedy at this time.
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