The triangle of death of neurons: Oxidative damage, mitochondrial dysfunction, and loss of choline-containing biomolecules in brains of mice treated with doxorubicin. Advanced insights into mechanisms of chemotherapy induced cognitive impairment (“chemobrain”) involving TNF-α

Xiaojia Ren, Jeriel T.R. Keeney, Sumitra Miriyala, Teresa Noel, David K. Powell, Luksana Chaiswing, Subbarao Bondada, Daret K. St. Clair, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Cancer treatments are developing fast and the number of cancer survivors could arise to 20 million in United State by 2025. However, a large fraction of cancer survivors demonstrate cognitive dysfunction and associated decreased quality of life both shortly, and often long-term, after chemotherapy treatment. The etiologies of chemotherapy induced cognitive impairment (CICI) are complicated, made more so by the fact that many anti-cancer drugs cannot cross the blood-brain barrier (BBB). Multiple related factors and confounders lead to difficulties in determining the underlying mechanisms. Chemotherapy induced, oxidative stress-mediated tumor necrosis factor-alpha (TNF-α) elevation was considered as one of the main candidate mechanisms underlying CICI. Doxorubicin (Dox) is a prototypical reactive oxygen species (ROS)-generating chemotherapeutic agent used to treat solid tumors and lymphomas as part of multi-drug chemotherapeutic regimens. We previously reported that peripheral Dox-administration leads to plasma protein damage and elevation of TNF-α in plasma and brain of mice. In the present study, we used TNF-α null (TNFKO) mice to investigate the role of TNF-α in Dox-induced, oxidative stress-mediated alterations in brain. We report that Dox-induced oxidative stress in brain is ameliorated and brain mitochondrial function assessed by the Seahorse-determined oxygen consumption rate (OCR) is preserved in brains of TNFKO mice. Further, we show that Dox-decreased the level of hippocampal choline-containing compounds and brain phospholipases activity are partially protected in TNFKO group in MRS study. Our results provide strong evidence that Dox-targeted mitochondrial damage and levels of brain choline-containing metabolites, as well as phospholipases changes decreased in the CNS are associated with oxidative stress mediated by TNF-α. These results are consistent with the notion that oxidative stress and elevated TNF-α in brain underlie the damage to mitochondria and other pathological changes that lead to CICI. The results are discussed with reference to our identifying a potential therapeutic target to protect against cognitive problems after chemotherapy.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalFree Radical Biology and Medicine
Volume134
DOIs
StatePublished - Apr 2019

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • Chemotherapy-induced cognitive impairment
  • Doxorubicin
  • MRS
  • Mitochondrial dysfunction
  • Oxidative stress
  • Phospholipases
  • Tumor necrosis factor-alpha

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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