Therapeutic potential of liver X receptor agonist GW3965 in preserving myelin integrity following traumatic brain injury.

BACKGROUND

Myelin, a multilamellar sheath produced by oligodendrocytes, ensures rapid electrical impulse conduction and maintains axonal integrity in the central nervous system (CNS). Demyelination, the loss or disruption of this protective sheath, is a key pathological consequence of traumatic brain injury (TBI) that exacerbates axonal injury and ultimately contributes to persistent cognitive and motor deficits. Currently, no therapies specifically target demyelination after TBI. Liver X receptors (LXRs) regulate lipid metabolism, cholesterol homeostasis, and inflammation in CNS cells. Activation of LXRs promotes oligodendrocyte maturation, enhances myelin gene expression, and facilitates remyelination. We hypothesized that GW3965, a synthetic LXR agonist, would enhance myelination and improved cognitive outcomes after TBI.

APPROACHES: C57BL/6 mice were subjected to mild TBI using a closed-head injury model and treated orally with GW3965 (10 mg·kg-1·day-1) starting 1 day post-injury for 3 weeks. Cognitive and behavioural performance was assessed using the modified Neurological Severity Score, open-field, novel object recognition, and Y-maze tests. On day 28 post-TBI, cortical tissues were analysed by immunofluorescence and a ProteinSimple® capillary-based immunoassay.

RESULTS

TBI caused sustained neurological and cognitive impairments characterized by demyelination, axonal injury, and neuronal loss. GW3965 treatment significantly preserved mature oligodendrocytes and myelin, reduced axonal degeneration, and improved behavioural performance.

CONCLUSIONS

This study provides novel insights into the role of LXR activation via GW3965 in mitigating TBI-induced demyelination and axonal injury, while preserving mature oligodendrocytes and cognitive and behavioural outcomes. These findings advance our understanding of brain repair mechanisms and highlight LXR activation as a promising therapeutic strategy for TBI-related neurological damage.