In vivo consequences of cholesterol-24S-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina.
Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina. We aimed to evaluate the consequences of CYP46A1 inhibition by voriconazole on cholesterol homeostasis and function in the retina. Rats received daily intraperitoneal injections of voriconazole (60mg/kg), minocycline (22mg/kg), voriconazole plus minocycline, or vehicle during five consecutive days. The rats were submitted to electroretinography to monitor retinal functionality. Cholesterol and 24S-hydroxycholesterol were measured in plasma, brain and retina by gas chromatography-mass spectrometry. The expression of CYP46A1, and GFAP as a marker for glial activation was analyzed in the retina and brain. Cytokines and chemokines were measured in plasma, vitreous, retina and brain. Voriconazole significantly impaired the functioning of the retina as exemplified by the reduced amplitude and increased latency of the b-wave of the electroretinogram, and altered oscillary potentials. Voriconazole decreased 24S-hydroxycholesterol levels in the retina. Unexpectedly, CYP46A1 and GFAP expression was increased in the retina of voriconazole-treated rats. ICAM-1 and MCP-1 showed significant increases in the retina and vitreous body. Minocycline did not reverse the effects of voriconazole. Our data highlighted the cross talk between retinal ganglion cells and glial cells in the retina, suggesting that reduced 24S-hydroxycholesterol concentration in the retina may be detected by glial cells, which were consequently activated.
INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France. Electronic address: cynthia.fourgeux@dijon.inra.fr.
Cynthia
C
Fourgeux
INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France.
Lucy
L
Martine
INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France.
Niyazi
N
Acar
INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; University Hospital, Department of Ophthalmology, F-21000 Dijon, France.
Alain M
AM
Bron
INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; University Hospital, Department of Ophthalmology, F-21000 Dijon, France.
Catherine P
CP
Creuzot-Garcher
INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, Eye and Nutrition Research Group, F-21000 Dijon, France; CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France.
Lionel
L
Bretillon
D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004596:Electroretinography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006888:Hydroxycholesterols / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D065819:Voriconazole
D016207:Cytokines; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D014230:Triazoles; C044563:24-hydroxycholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D065819:Voriconazole
CYP46A1; Cholesterol homeostasis; Glia; Retinal ganglion cell; Voriconazole