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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY006761-06
Application #
3263362
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1986-12-05
Project End
1995-11-30
Budget Start
1991-12-06
Budget End
1992-11-30
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Buchi, E R; Lam, T T; Suvaizdis, I et al. (1994) Injuries induced by diffuse photodynamic action in retina and choroid of albino rats. Morphologic study of an experimental model. Retina 14:370-8
Lam, T T; Fu, J; Chu, R et al. (1994) Intravitreal delivery of ganciclovir in rabbits by transscleral iontophoresis. J Ocul Pharmacol 10:571-5
Li, J; Edward, D P; Lam, T T et al. (1993) Amelioration of retinal photic injury by a combination of flunarizine and dimethylthiourea. Exp Eye Res 56:71-8
Takahashi, K; Lam, T T; Edward, D P et al. (1992) Protective effects of flunarizine on ischemic injury in the rat retina. Arch Ophthalmol 110:862-70
Fu, J; Lam, T T; Tso, M O (1992) Dexamethasone ameliorates retinal photic injury in albino rats. Exp Eye Res 54:583-94
Rosner, M; Lam, T T; Tso, M O (1992) Therapeutic parameters of methylprednisolone treatment for retinal photic injury in a rat model. Res Commun Chem Pathol Pharmacol 77:299-311
Rosner, M; Lam, T T; Fu, J et al. (1992) Methylprednisolone ameliorates retinal photic injury in rats. Arch Ophthalmol 110:857-61
Shahinfar, S; Edward, D P; Tso, M O (1991) A pathologic study of photoreceptor cell death in retinal photic injury. Curr Eye Res 10:47-59
Buchi, E R; Suivaizdis, I; Fu, J (1991) Pressure-induced retinal ischemia in rats: an experimental model for quantitative study. Ophthalmologica 203:138-47
Michon, J J; Li, Z L; Shioura, N et al. (1991) A comparative study of methods of photoreceptor morphometry. Invest Ophthalmol Vis Sci 32:280-4

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