Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice
- PDF / 7,073,189 Bytes
- 15 Pages / 595.276 x 790.866 pts Page_size
- 90 Downloads / 159 Views
Open Access
RESEARCH
Bexarotene normalizes chemotherapy‑induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice Angie C. A. Chiang1, Alexandre V. Seua1, Pooja Singhmar1, Luis D. Arroyo1, Rajasekaran Mahalingam1, Jian Hu2,3, Annemieke Kavelaars1 and Cobi J. Heijnen1*
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.
Introduction During the last decade cancer treatment has become more and more successful, but unfortunately a large number of cancer survivors reports long lasting neurotoxic *Correspondence: [email protected] 1 Division of Internal Medicine, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, 6355 MD Anderson Blvd, Unit 1055, Houston, TX 77030, USA Full list of author information is available at the end of the article
side effects of treatment, including cognitive impairment and sensory and motor abnormalities [28, 40, 41, 50, 51, 53, 54, 60]. There are no FDA-approved drugs to prevent or reverse these neurotoxicities. Therefore, development of novel therapeutic strategies is urgently needed. We 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]. At the structural level, these behavioral deficits are accompanied by a decrease
Data Loading...
