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24(S)-Hydroxycholesterol Protects the Ex Vivo Rat Retina From Injury by Elevated Hydrostatic Pressure

24(S)-Hydroxycholesterol Protects the Ex Vivo Rat Retina From Injury by Elevated Hydrostatic Pressure

Makoto Ishikawa, Takeshi Yoshitomi, Charles F Zorumski, Yukitoshi Izumi

Sci Rep. 2016 Sep 22;6:33886.

PMID: 27653972

Abstract:

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 μM 24(S)-HC. In contrast, voriconazole, a CYP46A1 inhibitor, was severely toxic even at normobaric pressure. Under normobaric conditions, 30 μM 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP474737	24(S)-Hydroxycholesterol		474-73-7	Price

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