title: 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.
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 alpha (TNF-alpha), 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.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA; Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: G
authors.initials: G
authors.lastname: Joshi
authors.forename: C D
authors.initials: CD
authors.lastname: Aluise
authors.forename: M P
authors.initials: MP
authors.lastname: Cole
authors.forename: R
authors.initials: R
authors.lastname: Sultana
authors.forename: W M
authors.initials: WM
authors.lastname: Pierce
authors.forename: M
authors.initials: M
authors.lastname: Vore
authors.forename: D K
authors.initials: DK
authors.lastname: St Clair
authors.forename: D A
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050050:Protein Carbonylation; D040901:Proteomics
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione