Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug adriamycin: implications for oxidative stress-mediated chemobrain

G. Joshi, C. D. Aluise, M. P. Cole, R. Sultana, W. M. Pierce, M. Vore, D. K. St Clair, D. A. Butterfield

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

Adriamycin (ADR) is a chemotherapeutic for the treatment of solid tumors. This quinone-containing anthracycline is well known to produce large amounts of reactive oxygen species (ROS) in vivo. A common complaint of patients undergoing long-term treatment with ADR is somnolence, often referred to as "chemobrain." While ADR itself does not cross the blood brain barrier (BBB), we recently showed that ADR administration causes a peripheral increase in tumor necrosis factor α (TNF-α), which migrates across the BBB and leads to inflammation and oxidative stress in brain, most likely contributing to the observed decline in cognition. In the current study, we measured levels of the antioxidant glutathione (GSH) in brains of mice injected intraparitoneally (i.p.) with ADR, as well as the levels and activities of several enzymes involved in brain GSH metabolism. We observed significantly decreased GSH levels, as well as altered GSH/GSSG ratio in brains of ADR treated mice relative to saline-treated controls. Also observed in brains of ADR treated mice were increased levels of glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR). We also observed increased activity of GPx, but a significant reduction in GST and GR activity in mice brain, 72 h post i.p. injection of ADR (20 mg/kg body weight). Furthermore, we used redox proteomics to identify specific proteins that are oxidized and/or have differential levels in mice brains as a result of a single i.p. injection of ADR. Visinin like protein 1 (VLP1), peptidyl prolyl isomerase 1 (Pin1), and syntaxin 1 (SYNT1) showed differential levels in ADR treated mice relative to saline-treated controls. Triose phosphate isomerase (TPI), enolase, and peroxiredoxin 1 (PRX-1) showed significantly increased specific carbonylation in ADR treated mice brain. These results further support the notion ADR induces oxidative stress in brain despite not crossing the BBB, and that antioxidant intervention may prevent ADR-induced cognitive dysfunction.

Original languageEnglish
Pages (from-to)796-807
Number of pages12
JournalNeuroscience
Volume166
Issue number3
DOIs
StatePublished - Mar 31 2010

Bibliographical note

Funding Information:
This work was supported in parts by funds from the Markey Cancer Center of the University of Kentucky and NIH grants to DSC [ AG-05119 ; CA-80152 ; CA-94853 ].

Keywords

  • adriamycin (doxorubicin)
  • chemobrain
  • glutathione
  • glutathione-related enzymes
  • oxidative stress
  • proteomics

ASJC Scopus subject areas

  • General Neuroscience

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