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Ischemic Preconditioning Attenuates Apoptotic Cell Death in the Rat Retina

¹ From the Department of Anesthesia and Critical Care, the ² Committees on Molecular Medicine and Neurobiology, and the ⁴ Pritzker School of Medicine, the University of Chicago, Chicago, Illinois; and the ³ Departments of Neurology, Neuroscience, and Ophthalmology, Albert Einstein College of Medicine, Bronx, New York.

PURPOSE. Ischemic preconditioning (IPC) protects the rat retina against the injury that ordinarily follows prolonged ischemia. It has been shown that release of adenosine, de novo protein synthesis, and mediators, such as protein kinase C and K_ATP channels, is required for IPC protection. However, the molecular mechanisms of neuroprotection by IPC are unknown. Retinal cells die after ischemia by necrosis and apoptosis. This study was undertaken to investigate the effect of IPC on apoptosis after ischemia and some of the key proteins involved in the apoptotic cascade.

METHODS. Retinal ischemia or IPC was produced in anesthetized Sprague-Dawley rats by increasing intraocular pressure above systolic arterial pressure. Retinal ischemia was induced 24 hours after either IPC or sham IPC. TUNEL staining was used to quantitate the number of cells with DNA fragmentation. The authors examined expression of cleaved forms of caspases-2 and -3, bax, and poly-adenosine diphosphate-ribose-polymerase (PARP) by Western blot analysis for evidence of apoptosis-related gene expression. To examine possible mechanisms of apoptosis after ischemia, the authors studied the expression of mitogen-activated protein kinases (MAP kinases). Functional recovery after ischemia was measured using electroretinography, and retinal histology was examined and quantitated by light microscopy.

RESULTS. Positive TUNEL staining, increases in caspase-2 and -3 cleavage, expression of bax and PARP, and activation of MAP kinases were found with ischemia. IPC attenuated these changes, but paradoxically, IPC itself triggered increased expression of MAP kinases.

CONCLUSIONS. IPC protects against ischemic injury, in part, by diminishing apoptosis-related gene expression and by altering protein phosphorylation.

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