Pifithrin-m prevents cisplatin-induced chemobrain by preserving neuronal mitochondrial function

Gabriel S. Chiu, Magdalena A. Maj, Sahar Rizvi, Robert Dantzer, Elisabeth G. Vichaya, Geoffroy Laumet, Annemieke Kavelaars, Cobi J. Heijnen

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

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 chemotherapyinduced 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-m 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-m 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. Ó2016 AACR.

Original languageEnglish (US)
Pages (from-to)742-752
Number of pages11
JournalCancer Research
Volume77
Issue number3
DOIs
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • High Resolution Electron Microscopy Facility

Fingerprint

Dive into the research topics of 'Pifithrin-m prevents cisplatin-induced chemobrain by preserving neuronal mitochondrial function'. Together they form a unique fingerprint.

Cite this