• Gabriel S Chiu, Magdalena A Maj, Sahar Rizvi, Robert Dantzer, Elisabeth G Vichaya, Geoffroy Laumet, Annemieke Kavelaars, and Cobi J Heijnen.
• Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
• Cancer Res. 2017 Feb 1; 77 (3): 742-752.

AbstractCognitive 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.©2016 American Association for Cancer Research.

33 keywords...

hide…