Abstract
Purpose:
We showed previously, in an inducible mouse model of open-angle glaucoma, that retinal ganglion cell (RGC) soma and axons could be robustly protected if preconditioned with repetitive systemic hypoxia prior to intraocular pressure (IOP) elevation, reflecting the presence of innate epigenetic mechanisms capable of enhancing RGC survival in this disease (Zhu Y et al., Mol Med 2012). The present study was undertaken to determine whether exposing mice to repetitive hypoxia after glaucoma onset ("postconditioning") could provide similar RGC protection.
Methods:
The IOP in one eye of adult male C57Bl/6 mice was chronically elevated to 20±2 mmHg by episcleral vein ligation (Zhu Y et al., Mol Med 2012; Zhu Y et al., IOVS 2013). Starting 3 d after IOP elevation, mice were exposed for 1 h to systemic hypoxia (11% oxygen), and this exposure was repeated seven times over the ensuing 3 wks (at 2-day or 3-day intervals); matched, randomized controls not postconditioned with hypoxia were also studied in parallel. After 3 wks of sustained intraocular hypertension, visual acuity was assessed bilaterally by optokinetic tracking. Thereafter, animals were sacrificed for RGC soma quantification in retinal flat mounts, and RGC axon quantification in postlaminar optic nerves, by NeuN and SMI32 immunohistochemistry, respectively.
Results:
In untreated controls, RGC soma loss was 20±2% (*p=0.002 vs. fellow eye), axon loss in the postlaminar optic nerve was 19±2% (*p <0.001 vs. fellow eye), and visual acuity was reduced 41% (*p=0.008 vs. baseline) after 3 wks of disease. However, in the postconditioned cohort, which exhibited the same magnitude of IOP elevation as untreated controls, RGC soma loss was only 8±2% (*p=0.002 vs. untreated controls), RGC axon loss was only 7±2% (*p <0.001 vs. untreated controls), and visual acuity was only reduced 11% (p=0.106 vs. untreated controls).
Conclusions:
Robust morphologic (>60% improvement) and functional (>72% improvement) protection of RGC soma and axons can be achieved after disease onset, and independent of IOP, by the protracted activation of endogenous cytoprotective mechanisms secondary to repetitive hypoxic stress. Thus, physiologic or pharmacologic stressors that induce and maintain epigenetic-based protective responses may serve as novel therapeutic strategies for enhancing RGC survival in patients with open-angle glaucoma.
Keywords: 615 neuroprotection •
449 cell survival •
531 ganglion cells