High dose
(S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer’s disease. Simultaneously,
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High dose
(S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer’s disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of
(S)-EFV. We have already tested (
rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer’s disease. Herein, we treated 5XFAD mice with (
rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid β
40 peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (
rac)-7,8dihydroxy EFV were weaker than those of EFV and (
rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (
rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (
rac)-7,8dihydroxy EFV or (
rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite.
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