Cholesterol-Dependent LXR Transcription Factor Activity Represses Pronociceptive Effects of Estrogen in Sensory Neurons and Pain Induced by Myelin Basic Protein Fragments

Authors

Swathi K Hullugundi
Jennifer Dolkas
Andrei V Chernov
Tony L Yaksh
Kelly A Eddinger
Mila Angert
Glaucilene Ferreira Catroli
Alex Y Strongin
Patrick M Dougherty
Yan Li
Oswal Quehenberger
Aaron Armando
Veronica I Shubayev

Publication Date

7-1-2024

Journal

Brain, Behavior, & Immunity - Health

Abstract

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP

METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP

RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP

CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

Keywords

Neuropathic pain, Oxysterol, Cholesterol, Liver x receptor, LXR, Myelin basic protein, Estrogen, Interleukin 6, DRG culture, Sensory neuron

Comments

Supplementary Materials

PMID: 38590761