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Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.
- Source :
-
Acta neuropathologica communications [Acta Neuropathol Commun] 2020 Nov 12; Vol. 8 (1), pp. 193. Date of Electronic Publication: 2020 Nov 12. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Antineoplastic Agents toxicity
Chemotherapy-Related Cognitive Impairment metabolism
Chemotherapy-Related Cognitive Impairment pathology
Chemotherapy-Related Cognitive Impairment physiopathology
Gait drug effects
Gene Expression Profiling
Gyrus Cinguli metabolism
Gyrus Cinguli pathology
Gyrus Cinguli physiopathology
Mice
Myelin Sheath metabolism
Myelin Sheath pathology
Myelin Sheath ultrastructure
Netrins drug effects
Netrins genetics
Netrins metabolism
Neuregulins drug effects
Neuregulins genetics
Neuregulins metabolism
Open Field Test
Prefrontal Cortex drug effects
Prefrontal Cortex metabolism
Prefrontal Cortex pathology
Prefrontal Cortex physiopathology
RNA-Seq
Retinoid X Receptors drug effects
Retinoid X Receptors genetics
Retinoid X Receptors metabolism
Sensorimotor Cortex metabolism
Sensorimotor Cortex pathology
Sensorimotor Cortex physiopathology
White Matter drug effects
White Matter metabolism
White Matter pathology
Antineoplastic Agents pharmacology
Bexarotene pharmacology
Cisplatin toxicity
Cognition drug effects
Gyrus Cinguli drug effects
Myelin Sheath drug effects
Psychomotor Performance drug effects
Sensorimotor Cortex drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2051-5960
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Acta neuropathologica communications
- Publication Type :
- Academic Journal
- Accession number :
- 33183353
- Full Text :
- https://doi.org/10.1186/s40478-020-01061-x