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Mohammad Dehabadi, Benjamin M Davis, Eduardo Maria Normando, Li Guo, Shereen Nizari, Lisa Turner, M Francesca Cordeiro; The Natural History of Apoptotic and Necrotic Cell Death in a Rat Model of Ocular Hypertension. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2417.
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Apoptosis, or programmed cell death, is a tightly controlled and orchestrated process. It is an essential event in both normal development, and maintenance of tissue function. Both apoptosis and necrosis have proven to be central in acute and chronic degenerative processes. The role of different modes of cell death has not been studied in vivo. In a rat ocular hypertension model, we performed in vivo imaging using spectrally distinct, well recognized fluorescent cell death markers to measure the amount of early and late apoptosis, as well as necrosis at various time points post insult.
A well-established rodent model of ocular hypertension was used. Animals were imaged at 1, 3, and 8 week timepoints post IOP elevation and the number of retinal cells undergoing early apoptosis (IR labeled Annexin-A5), late apoptosis (Annexin-A5 & Propidium Iodide co-labelling), and necrosis (Propidium Iodide labeled only) were quantified using image analysis by a blinded grader.
The absolute peak of cell death labelling was found to occur at 1 week post IOP elevation, and was greatly diminished by 8 weeks. The greatest Annexin-5 labeling was found at 1 week, with early apoptosis significantly reduced by 8 weeks (p=0.02). Cell necrosis was found to peak at 3 weeks, and was the predominant form of cell death at 8 weeks. Fewer cells were in late apoptosis compared to early apoptosis (p= 0.02 at 1, p= 0.07 at 3, and p= 0.09 at 8 weeks) and necrosis (p<0.001 at 1 & 3 weeks, p=0.3 at 8 weeks).
Early apoptosis was seen to occur very early in this model, with necrosis predominating at 8 weeks. Early apoptosis is recognized to be a potentially reversible phase, and this study suggests its occurrence could be targeted if identified early enough. These findings could have important implications in the study of neuroprotection in glaucoma, especially the timing of potential curative therapies.
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