Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain.
Adriamycin (ADR), a potent anti-tumor agent, produces reactive oxygen species (ROS) in cardiac tissue. Treatment with ADR is dose-limited by cardiotoxicity. However, the effect of ADR in the other tissues, including the brain, is unclear because ADR does not pass the blood-brain barrier. Some cancer patients receiving ADR treatment develop a transient memory loss, inability to handle complex tasks etc., often referred to by patients as chemobrain. We previously demonstrated that ADR causes CNS toxicity, in part, via systemic release of cytokines and subsequent generation of reactive oxygen and nitrogen species (RONS) in the brain. Here, we demonstrate that treatment with ADR led to an increased circulating level of tumor necrosis factor-alpha in wild-type mice and in mice deficient in the inducible form of nitric oxide (iNOSKO). However, the decline in mitochondrial respiration and mitochondrial protein nitration after ADR treatment was observed only in wild-type mice, not in the iNOSKO mice. Importantly, the activity of a major mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), was reduced and the protein was nitrated. Together, these results suggest that NO is an important mediator, coupling the effect of ADR with cytokine production and subsequent activation of iNOS expression. We also identified the mitochondrion as an important target of ADR-induced NO-mediated CNS injury.
Tangpong
Jitbanjong
J
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, USA.
Cole
Marsha P
MP
Sultana
Rukhsana
R
Estus
Steven
S
Vore
Mary
M
St Clair
William
W
Ratanachaiyavong
Suvina
S
St Clair
Daret K
DK
Butterfield
D Allan
DA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods; D001923:Brain Chemistry / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013482:Superoxide Dismutase / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase