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Cynthia Fourgeux, Lucy Martine, Bruno Pasquis, Niyazi Acar, Alain M. Bron, Catherine P. Garcher, Lionel Bretillon; In Vivo Consequences Of Cholesterol-24s-hydroxylase (CYP46A1) Inhibition By Voriconazole On Cholesterol Homeostasis And Function In The Rat Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):519.
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Cholesterol 24S-hydroxylase (CYP46A1) is an enzyme which converts cholesterol into 24S-hydroxycholesterol (24SOH) in neurons and participates to cholesterol homeostasis in the central nervous system including the retina. Voriconazole is an antifungal antiobiotic which inhibits the activity of CYP46A1. The purpose of our study was to evaluate the consequences of CYP46A1 inhibition by voriconazole on cholesterol homeostasis and function in the retina.
Sprague-Dawley rats received five intraperitoneal injections of voriconazole (60mg/kg, once a day). The rats were submitted to electroretinogram to monitor functionality of the retina. Cholesterol and 24SOH were measured in plasma, brain and retina by isotope dilution gas chromatography-mass spectrometry using internal deuterated standard. Immunostaining were carried out to analyze the expression of CYP46A1, GFAP, CD11b as markers for glial activation in the retina and brain. Cytokines and chemokines were measured by Luminex® in plasma, retinal and brain homogenates.
Voriconazole treatment significantly impaired the functioning of the retina as exemplified by the reduced amplitude and increased latency of the b-wave of the electroretinogram. Meanwhile, oscillary potentials and scotopic threshold response were altered in voriconazole-treated animals. Cholesterol concentration was reduced by half in the retina and did not vary in the brain. 24S-OH levels decreased by 18% in the retina and 42% in the brain. Plasma cholesterol and 24SOH concentration remained unchanged by voriconazole. Unexpectedly, CYP46A1 expression was increased in the retina and brain (x1.5). Meanwhile, GFAP expression was raised by a factor of 3.7 and 1.4 in the retina and brain, respectively, after voriconazole treatment.
Voriconazole was found to inhibit cholesterol and 24S-OH synthesis in the retina, and to impair the functioning of the retina. Gliosis may participate to the maintenance of 24SOH levels in the central nervous system, including the retina in which glial activation reached greater level of magnitude than in the brain.
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