Purchase this article with an account.
J.M. Gidday, B.K. McMahan, Y. Zhu; Long-lasting Neuroprotection Induced in Mouse Retina by Repeated Hypoxic Preconditioning . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2942.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
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.
This PDF is available to Subscribers Only