Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: Insight into the mechanism of chemobrain

Jitbanjong Tangpong, Marsha P. Cole, Rukhsana Sultana, Steven Estus, Mary Vore, William St. Clair, Suvina Ratanachaiyavong, Daret K. St. Clair, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)191-201
Number of pages11
JournalJournal of Neurochemistry
Volume100
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Adriamycin-induced chemobrain
  • Central nervous system toxicity
  • Inducible nitric oxide synthase knockout mice
  • Manganese superoxide dismutase
  • Mitochondrial respiration
  • Nitric oxide

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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