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P.S. Rosenbaum, S. Nijhawan, S. Malhotra, H. Zhang, D.M. Rosenbaum; Caspase Activation May be Triggered by the Intrinsic (Mitochondria–Mediated) Cell Death Pathway in Response to Retinal Ischemia . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3276.
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Purpose:Inhibition of caspases has been suggested as a potential neuroprotective strategy for disorders in which ischemia plays a pathogenetic role. We have previously demonstrated the role of the intrinsic (mitochondria–mediated) cell death pathway in a model of ischemia–reperfusion in the rat retina. The purpose of this study was to characterize the caspases involved in retinal cell death in this same model. Methods:Transient retinal ischemia was induced in Sprague–Dawley rats by increasing intraocular pressure above systolic arterial pressure for 60 minutes. TUNEL staining was performed to identify those cells undergoing DNA fragmentation. The spatial and temporal patterns of caspase 3, 7, 9, as well as APAF–1 and cytochrome c was determined in the retina following ischemic injury. Double–labeling with cell–specific markers (Thy1, PKC, HPC–1, GFAP) identified which cells were expressing these various different apoptosis–related proteins. Results:Maximal expression of all three caspases as well as APAF–1 and cytochrome c were found at 24 hours in all retinal cell types coinciding with maximal TUNEL–positivity. However, expression of caspase 9 was seen as early as three hours following ischemia and expression of APAF–1 and cytochrome c was noted as early as six hours following ischemia (these three proteins are the major constituents of the apoptosome). Caspases 3, 7, 9 were expressed earlier in retinal neurons than in GFAP–positive cells. Conclusions:These data support the importance of caspases in retinal cell death secondary to ischemia–reperfusion. Furthermore, these data support the critical role of the intrinsic cell death pathway in this animal model. Therapies aimed at inhibiting this pathways offer potential targets for therapeutic strategies for ischemic retinal disorders.
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