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JM Gidday, BK McMahan, Y Zhu; Prolonged State of Retinal Ischemic Tolerance in Mice Following Hypoxic Preconditioning . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3304.
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Purpose: We developed a model of retinal ischemic tolerance in mice (Zhu et al., IOVS, submitted) in which preconditioning with a brief period of retinal ischemia by optic nerve bundle compression induced tolerance to retinal ischemic injury when induced 24 h later. However, this period of tolerance was not sustained at 72 h. Herein, we studied whether systemic hypoxia as a preconditioning stimulus would promote a longer lasting period of retinal ischemic tolerance. Methods: Retinal ischemic injury was induced in one eye of adult male Swiss-Webster ND4 mice by elevating IOP to 90 mmHg for 30 min under chloral hydrate anesthesia. Subsets of animals were preconditioned at 1, 3, or 7 days prior to this ischemic insult with systemic hypoxia by placing the animals in a container flushed with 11% oxygen for 2 h. Retinal injury was quantified one week after retinal ischemia by histopathologic analyses of H&E-stained 5-µm sections of paraffin-embedded retinae; the number of surviving cells in the INL and GCL was quantified at a set distance from the optic nerve in all four quadrants. Results: In nonpreconditioned animals (n=7), 25% and 33% of cells were lost in the INL and GCL, respectively, in response to the ischemic insult. However, preconditioning with systemic hypoxia resulted in the near complete survival of cells in both inner retinal layers, even when the preconditioning stimulus preceded the ischemic insult by one week (n=7). Studies are underway to identify when this period of robust tolerance transpires. Conclusion: These and our previous findings indicate that the characteristics of ischemic tolerance depend on the preconditioning stimulus used to promote it. Understanding the endogenous mechanisms responsible for the long-lasting protection of these cells may have clinical implications for glaucoma and various ischemic retinopathies.
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