Research Papers:

Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”)

Jeriel T.R. Keeney, Xiaojia Ren, Govind Warrier, Teresa Noel, David K. Powell, Jennifer M. Brelsfoard, Rukhsana Sultana, Kathryn E. Saatman, Daret K. St. Clair and D. Allan Butterfield _

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Oncotarget. 2018; 9:30324-30339. https://doi.org/10.18632/oncotarget.25718

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Jeriel T. R. Keeney1,*, Xiaojia Ren1,*, Govind Warrier1, Teresa Noel2, David K. Powell3, Jennifer M. Brelsfoard4, Rukhsana Sultana1, Kathryn E. Saatman4, Daret K. St. Clair2,5,6 and D. Allan Butterfield1,6,7

1Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA

2Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA

3Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky Medical Center, Lexington, KY 40536, USA

4Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA

5Department of Radiation Medicine, University of Kentucky, Lexington, KY 40502, USA

6Markey Cancer Center, University of Kentucky, Lexington, KY 40502, USA

7Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA

*Co-first authors

Correspondence to:

D. Allan Butterfield, email: [email protected]

Keywords: chemotherapy induced cognitive impairment; oxidative stress; choline; cognitive dysfunction

Received: December 19, 2017     Accepted: June 13, 2018     Published: July 13, 2018


Chemotherapy-induced cognitive impairment (CICI) is now widely recognized as a real and too common complication of cancer chemotherapy experienced by an ever-growing number of cancer survivors. Previously, we reported that doxorubicin (Dox), a prototypical reactive oxygen species (ROS)-producing anti-cancer drug, results in oxidation of plasma proteins, including apolipoprotein A-I (ApoA-I) leading to tumor necrosis factor-alpha (TNF-α)-mediated oxidative stress in plasma and brain. We also reported that co-administration of the antioxidant drug, 2-mercaptoethane sulfonate sodium (MESNA), prevents Dox-induced protein oxidation and subsequent TNF-α elevation in plasma. In this study, we measured oxidative stress in both brain and plasma of Dox-treated mice both with and without MESNA. MESNA ameliorated Dox-induced oxidative protein damage in plasma, confirming our prior studies, and in a new finding led to decreased oxidative stress in brain. This study also provides further functional and biochemical evidence of the mechanisms of CICI. Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits, an effect that was rescued by MESNA. Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline-containing compounds assessed by (Cho)/creatine ratios in the hippocampus in mice. To better elucidate a potential mechanism for this MRS observation, we tested the activities of the phospholipase enzymes known to act on phosphatidylcholine (PtdCho), a key component of phospholipid membranes and a source of choline for the neurotransmitter, acetylcholine (ACh). The activities of both phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D were severely diminished following Dox administration. The activity of PC-PLC was preserved when MESNA was co-administered with Dox; however, PLD activity was not protected. This study is the first to demonstrate the protective effects of MESNA on Dox-related protein oxidation, cognitive decline, phosphocholine (PCho) levels, and PC-PLC activity in brain and suggests novel potential therapeutic targets and strategies to mitigate CICI.

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