Abstract
Abstract: :
Purpose: We showed previously in mice that a transient period of ischemic tolerance, wherein retinal neurons are resistant to ischemia, can be promoted by a preceding exposure to a nonlethal ischemic or hypoxic preconditioning (HPC) stimulus (Zhu et al. IOVS 43: 1903-1911, 2002). Although robust, the adaptive response to a single PC stimulus lasts only 1-3 days. The goal of the present study was to test the hypothesis that multiple bouts of HPC can increase the duration of the ischemia-tolerant state. Methods: Conscious, adult male Swiss-Webster ND4 mice received HPC (2 h systemic hypoxia; 11% oxygen) three times per week (once every other day) for one or two weeks; 30 min of retinal ischemia (elevated IOP) was induced 2, 4, or 8 weeks after the last HPC stimulus. At one week postischemia, eyes were perfusion-fixed, paraffin-embedded, and thin-sectioned for detailed histopathologic analysis of retinal injury. Some animals were killed immediately after HPC for analysis of retinal hypoxia-inducible factor-1 alpha (HIF-1α) expression by immunocytochemistry. Results: Thirty min ischemia reduced the thickness of the INL, IPL, and the entire inner retina (OLM-ILM) by 17, 24, and 20%, respectively, and reduced cell counts in the INL and GCL by 22, and 27%, respectively. Significant ischemic tolerance (all variables not significantly different from nonischemic controls) was present 2 and 4 weeks after the one-week HPC regimen, with protection ranging from 75-100%. The two-week HPC regimen resulted in near complete preservation (100% protection) of INL and GCL cell counts and IPL thickness 8 weeks after the last HPC; INL thickness and OLM-ILM thickness was reduced at 8 weeks, but still significantly protected by 40-50%. At the end of both the single and multiple HPC treatments, HIF-1α expression was induced in cells of the GCL and INL. Conclusions: A prolonged phenotypic change in retinal ischemic resistance can be established by repeated HPC. Transcriptional activation of HIF-1α target genes may be involved in the neuroprotection so induced. A more complete understanding the endogenous adaptive mechanisms that underlie this protracted neuroprotective phenotype may have therapeutic utility for preventing retinal injury in glaucoma and other ischemic retinopathies.
Keywords: ganglion cells • ischemia • transcription factors