Pifithrin-µ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function.
Cancer Res
; 77(3): 742-752, 2017 02 01.
Article
in En
| MEDLINE
| ID: mdl-27879267
ABSTRACT
Cognitive impairment, termed chemobrain, is a common neurotoxicity associated with chemotherapy treatment, affecting an estimated 78% of patients. Prompted by the hypothesis that neuronal mitochondrial dysfunction underlies chemotherapy-induced cognitive impairment (CICI), we explored the efficacy of administering the small-molecule pifithrin (PFT)-µ, an inhibitor of mitochondrial p53 accumulation, in preventing CICI. Male C57BL/6J mice injected with cisplatin ± PFT-µ for two 5-day cycles were assessed for cognitive function using novel object/place recognition and alternation in a Y-maze. Cisplatin impaired performance in the novel object/place recognition and Y-maze tests. PFT-µ treatment prevented CICI and associated cisplatin-induced changes in coherency of myelin basic protein fibers in the cingular cortex and loss of doublecortin+ cells in the subventricular zone and hippocampal dentate gyrus. Mechanistically, cisplatin decreased spare respirator capacity of brain synaptosomes and caused abnormal mitochondrial morphology, which was counteracted by PFT-µ administration. Notably, increased mitochondrial p53 did not lead to cerebral caspase-3 activation or cytochrome-c release. Furthermore, PFT-µ administration did not impair the anticancer efficacy of cisplatin and radiotherapy in tumor-bearing mice. Our results supported the hypothesis that neuronal mitochondrial dysfunction induced by mitochondrial p53 accumulation is an underlying cause of CICI and that PFT-µ may offer a tractable therapeutic strategy to limit this common side-effect of many types of chemotherapy. Cancer Res; 77(3); 742-52. ©2016 AACR.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sulfonamides
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Brain
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Cisplatin
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Neuroprotective Agents
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Neurons
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Antineoplastic Agents
Limits:
Animals
Language:
En
Journal:
Cancer Res
Year:
2017
Type:
Article