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Adriamycin‐mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain
Author(s) -
Tangpong Jitbanjong,
Cole Marsha P.,
Sultana Rukhsana,
Estus Steven,
Vore Mary,
St. Clair William,
Ratanachaiyavong Suvina,
St. Clair Daret K.,
Butterfield D. Allan
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04179.x
Subject(s) - superoxide dismutase , nitric oxide , reactive oxygen species , pharmacology , superoxide , central nervous system , mitochondrion , reactive nitrogen species , nitric oxide synthase , antioxidant , peroxynitrite , tumor necrosis factor alpha , chemistry , medicine , biochemistry , enzyme
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.