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In the central nervous system, 24(S)-hydroxycholesterol (24(S)-HC) is an oxysterol synthesized from cholesterol by cholesterol 24-hydroxylase (CYP46A1) encoded by the cyp46a1 gene. In the present study using a rat ex vivo glaucoma model, we found that retinal 24(S)-HC synthesis is facilitated by pressure elevation. Moreover, we found that 24(S)-HC is neuroprotective against pressure mediated retinal degeneration. Quantitative real-time RT-PCR, ELISA, and immunohistochemistry revealed that elevated pressure facilitated the expression of cyp46a1 and CYP46A1. Immunohistochemically, the enhanced expression of CYP46A1 was mainly observed in retinal ganglion cells (RGC). LC-MS/MS revealed that 24(S)-HC levels increased in a pressure-dependent manner. Axonal injury and apoptotic RGC death induced by 75 mmHg high pressure was ameliorated by exogenously administered 1 mu M 24(S)-HC. In contrast, voriconazole, a CYP46A1 inhibitor, was severely toxic even at normobaric pressure. Under normobaric conditions, 30 mu M 24(S)-HC was required to prevent the voriconazole-mediated retinal damage. Taken together, our findings indicate that 24(S)-HC is facilitated by elevated pressure and plays a neuroprotective role under glaucomatous conditions, while voriconazole, an antifungal drug, is retinotoxic. 24(S)-HC and related compounds may serve as potential therapeutic targets for protecting glaucomatous eyes from pressure-induced injuries.

In a rat ex vivo acute glaucoma model, high pressure (75 mmHg) causes swelling of ganglion cell axons and elevates levels of the endogenous steroids 24(S)-hydroxycholesterol (24SH) and allopregnanolone (AlloP). Furthermore, 24SH (0.1 mu M) alone elevates AlloP levels via NMDA receptors. With this model, we now investigate possible interactions between 24SH and AlloP. We found that inhibition of AlloP synthesis with dutasteride under high pressure results in severe excitotoxicity in addition to axonal swelling. The excitotoxicity is prevented by exogenous AlloP but not 24SH, indicating that endogenous AlloP is crucial for protection. However, inhibition of 24SH synthesis with voriconazole induces severe excitotoxicity under normal pressure. Paradoxically, the excitotoxicity by voriconazole is better prevented by AlloP than 24SH. These findings suggest that inhibition of 24SH synthesis becomes excitotoxic in the absence of AlloP. We also observed that co-administration of sub-micromolar 24SH (0.1 mu M) and AlloP (0.1 mu M), concentrations that are only partially effective when administered alone, prevents axonal swelling under high pressure. This apparent enhanced protection indicates strong interaction between the two neurosteroids to preserve neuronal integrity, with 24SH contributing to AlloP synthesis via NMDA receptors and with AlloP playing an essential role in neuroprotection via GABA(A) receptors.

Purpose The influence of myopia on glaucoma progression remains unknown, possibly because of the multifactorial nature of glaucoma and difficulty in assessing a solo contribution of myopia. The purpose of this study is to investigate the association of myopia with visual field (VF) progression in glaucoma using a paired-eye design to minimize the influence of confounding systemic factors that are diverse among individuals. Methods This retrospective study evaluated 144 eyes of 72 subjects with open-angle glaucoma, with similar intra-ocular pressure between paired eyes, spherical equivalent (SE) <= -2 diopter (D), and axial length >= 24 mm. Paired eyes with faster and slower VF progression were grouped separately, according to the global VF progression rate assessed by automated pointwise linear regression analysis. The SE, axial length, tilt ratio and torsion angle of optic discs, Bruch's membrane (BM) opening area, and gamma zone parapapillary atrophy (PPA) width were compared between the two groups. Factors associated with faster VF progression were determined by logistic regression analysis. Results The mean follow-up duration was 8.9 +/- 4.4 years. The mean value of SE and axial length were -6.31 +/- 1.88 D and 26.05 +/- 1.12 mm, respectively. The mean global visual field progression rate was -0.32 +/- 0.38 dB/y. Tilt ratio, BM opening area, and gamma zone PPA width were significantly greater in the eyes with faster VF progression than those with slower progression. In multivariate analysis, these factors were significantly associated with faster VF progression (all P < 0.05), while SE and axial length were not associated with it. Conclusion In myopic glaucoma subjects, tilt of the optic disc and temporal shifting and enlargement of the BM opening were associated with faster rate of VF progression between paired eyes. This suggests that myopia influences VF progression in glaucomatous eyes via optic disc deformations rather than via refractive error itself.

Purpose To examine the association of myopia with the visual field (VF) defects in open-angle glaucoma (OAG) using paired eyes to eliminate the effect of unknown confounding factors that are diverse among individuals. Methods One hundred eighteen eyes of 59 subjects with myopia (spherical equivalent [SE] >= -2 diopter [D] and axial length >= 24.0 mm) whose intra-ocular pressure between paired eyes was similar and the mean deviation (MD) of the Humphrey VF test differed by more than 6 dB were included. Refractive errors (SE, axial length) and parameters associated with the papillary and parapapillary myopic deformation (tilt ratio, torsion angle, and beta-zone parapapillary atrophy [PPA] area without Bruch's membrane) were measured in each eye. The paired eyes were divided into worse and better eyes according to the MD of the VF, and parameters were compared between them. Further, multiple linear regression analysis was performed to examine the correlation of the difference in various parameters with the MD difference between paired eyes. Results The SE of all eyes was -6.39 +/- 2.15 D (mean +/- standard deviation) and axial length was 26.42 +/- 1.07 mm. MD of the worse and better VF eyes were -13.56 +/- 6.65 dB and -4.87 +/- 5.32 dB, respectively. Eyes with worse VFs had significantly greater SE, axial length, tilt ratio, and PPA area without Bruch's membrane than those with better VFs (all P < 0.05). In multiple linear regression analysis, the difference of the MD between paired eyes was significantly correlated with the difference in the tilt ratio and PPA area without Bruch's membrane. Conclusion The myopic papillary and parapapillary deformations, but not refractive error itself, were related to the worse VF in paired eyes with OAG. This suggests that myopia influences the severity of the glaucomatous VF defects via structural deformation.