CYP46A1-Targeted Treatment Alleviates Long-Term White Matter Injury Following Traumatic Brain Injury by Promoting...

Area of Science:

• Neuroscience
• Biochemistry
• Traumatology

Background:

• Cholesterol is vital for white matter injury (WMI) repair post-traumatic brain injury (TBI).
• Cholesterol 24-hydroxylase (CYP46A1) regulates cholesterol metabolism via 24(S)-hydroxycholesterol (24OHC) production.
• CYP46A1's role in TBI-induced WMI is not well understood.

Purpose of the Study:

• To investigate the function of CYP46A1 in TBI-induced WMI.
• To explore the therapeutic potential of activating CYP46A1 for TBI recovery.

Main Methods:

• Controlled cortical impact model of TBI in adult male C57BL/6 mice.
• Utilized CYP46A1 activator efavirenz and CYP46A1 knockout mice.
• Assessed neurological function, WMI, cholesterol metabolism, microglial activity, and remyelination.

Main Results:

• Efavirenz treatment improved neurological function and preserved white matter structure post-TBI.
• Efavirenz enhanced microglial debris clearance and oligodendrocyte precursor cell remyelination.
• Efavirenz increased 24OHC levels, activated liver X receptors (LXR), and promoted cholesterol export, with partial reduction in efficacy upon CYP46A1 knockdown or LXR blockade.

Conclusions:

• Efavirenz administration promotes neurological recovery and white matter integrity following TBI.
• CYP46A1 activation facilitates WMI repair through cholesterol homeostasis regulation and enhanced remyelination.