Abstract
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.
Highlights
During the last decade cancer treatment has become more and more successful, but a large number of cancer survivors reports long lasting neurotoxicWe have recently shown that treatment of mice with cisplatin induces a profound and long lasting impairment in performance in tasks of spatial memory and executive functioning [5, 7, 8, 35, 65]
We examined the impact of cisplatin treatment on ultrastructural changes in myelin within the prefrontal cortex by transmission electron microscopy (TEM)
We observed ultrastructural myelin abnormalities characterized by an increased percentage of axons with split sheathes and myelin decompaction in cisplatintreated mice (Fig. 1a, b)
Summary
During the last decade cancer treatment has become more and more successful, but a large number of cancer survivors reports long lasting neurotoxicWe have recently shown that treatment of mice with cisplatin induces a profound and long lasting impairment in performance in tasks of spatial memory and executive functioning [5, 7, 8, 35, 65]. Myelin is produced by oligodendrocytes, while astrocytes, T cells and macrophages/microglia can all modulate myelin formation [15, 29, 45]. As a common binding partner of many other nuclear receptors, it mainly functions as a ligand-dependent transcription factor and regulates many physiological processes. Activation of the RXR family of receptors can promote (re)myelination either via their anti-inflammatory effect, their effects on monocyte/macrophage phagocytosis of myelin to remove myelin debris, and for their capacity to directly stimulate oligodendrocyte precursor proliferation/differentiation [9, 12, 39]. RXR activation, either via genetic manipulation or pharmacologic interventions, increased oligodendrocyte differentiation and remyelination in models of toxin-induced demyelination in rats [25]. Transcripts encoding RXRγ were upregulated during remyelination and expressed by cells of the oligodendrocyte lineage [25]
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