Reductions in Retinal Ganglion Cell Loss by Repetitive Hypoxic Preconditioning in a Mouse Model of Glaucoma

Abstract

Abstract: : Purpose: We showed previously that repetitive preconditioning of adult mice by six brief exposures to systemic hypoxia over a two–week period protects against acute ischemic injury in retina and that this neuroprotective phenotype is sustained up to eight weeks after the last preconditioning treatment (Gidday et al., ARVO 2003, #2942). In the present study, we assessed whether the establishment of a long–lasting period of ischemic tolerance would also protect against the progressive loss of retinal ganglion cells that occurs with glaucoma. Methods: Episcleral vein cauterization was performed in one eye of C57Bl/6 mice, which leads to significant elevations in IOP 1 day to 4 weeks thereafter. Cauterization was performed on one group of mice that completed the repetitive hypoxic preconditioning (RHP) protocol 3 days earlier, while another group of mice was subjected to cauterization without preconditioning. Surviving retinal ganglion cells (RGCs) were quantified in the middle to mid–periphery regions of all quadrants at three weeks of IOP elevation in retinal flat mounts using brn–3b immunolabelling and image analysis. Results: A significant reduction (22–28%) of RGC immunoreactivity was found in retinae of glaucomatous eyes relative to retinae of contralateral eyes, indicative of RGC cell loss. RHP resulted in a significant preservation (42–55%) of RGC immunoreactivity in glaucomatous eyes. Conclusions: Loss of RGCs in glaucoma can be significantly reduced by RHP, indicating that RHP activates endogenous neuroprotective pathways that result in increased RGC survival in glaucoma. The mechanisms underlying this adaptive cytoprotective response may represent novel therapeutic targets for clinical application in glaucoma.

Keywords: ganglion cells • neuroprotection • pathology: experimental