# 7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite

## TL;DR

This study compares the brain effects of a dihydroxy metabolite of efavirenz with the drug itself and another metabolite in a mouse model of Alzheimer’s disease.

## Contribution

The study reveals that 7,8-dihydroxy efavirenz is less effective than efavirenz or 8,14-dihydroxy efavirenz in activating CYP46A1 and improving Alzheimer’s-related brain markers.

## Key findings

- 7,8-dihydroxy efavirenz modestly activated CYP46A1 and increased acetyl-CoA and acetylcholine in the brain.
- Male mice showed reduced levels of insoluble amyloid β40, but no cognitive improvements were observed.
- The effects of 7,8-dihydroxy efavirenz were weaker than those of efavirenz or 8,14-dihydroxy efavirenz.

## Abstract

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 β40 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.