Bexarotene Normalizes Chemotherapy-induced Myelin Decompaction and Reverses Cognitive and Sensorimotor Deficits in Mice

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.