Adriamycin-induced, TNF-α-mediated central nervous system toxicity

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

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

The clinical effectiveness of adriamycin (ADR), a potent chemotherapeutic, is known to be limited by severe cardiotoxic side effects. However, the effect of ADR on brain tissue is not well understood. It is generally thought that ADR is not toxic to the brain because ADR does not pass the blood-brain barrier. The present study demonstrates that ADR autofluorescence was detected only in areas of the brain located outside the blood-brain barrier, but a strong tumor necrosis factor (TNF) alpha immunoreactivity was detected in the cortex and hippocampus of ADR-treated mice. Systemic injection of ADR led to a decline in brain mitochondrial respiration via complex I substrate shortly after ADR treatment (P < 0.05). Cytochrome c release, increased caspase 3 activity, and TUNEL-positive cell death all were suggestive of apoptosis in brain following systemic ADR treatment. The levels of the known pro-apoptotic proteins, p53 and Bax, were increased in brain mitochondria at 3 h following ADR treatment and declined by 48 h. In contrast, the anti-apoptotic protein, Bcl-xL, was increased later at 6 h post-ADR treatment and was sustained throughout 72 h. Furthermore, p53 migrated to mitochondria and interacted with Bcl-xL, supporting the hypothesis that mitochondria are targets of ADR-induced CNS injury. Neutralizing antibodies against circulating TNF completely abolished both the increased TNF in the brain and the observed mitochondrial injury in brain tissues. These results are consistent with the notion that TNF is an important mediator by which ADR induces central nervous system (CNS) injury. This study, the first to provide direct biochemical evidence of ADR toxicity to the brain, revealed novel mechanisms of ADR-induced CNS injury and suggests a potential therapeutic intervention against circulating TNF-induced CNS effects.

Original languageEnglish
Pages (from-to)127-139
Number of pages13
JournalNeurobiology of Disease
Volume23
Issue number1
DOIs
StatePublished - Jul 2006

Bibliographical note

Funding Information:
Jitbanjong Tangpong is partially supported by The Ministry of University Affairs of Thailand under the Faculty Development Program.

Funding Information:
This work was supported, in part, by NIH grants to DAB [AG-10836, AG-05119] and DSC [AG-05119, CA-80152, and CA-94853].

Keywords

  • Adriamycin
  • Bcl-xL
  • Central nervous system
  • Chemobrain
  • Mitochondrial respiration
  • Tumor necrosis factor alpha
  • p53

ASJC Scopus subject areas

  • Neurology

Fingerprint

Dive into the research topics of 'Adriamycin-induced, TNF-α-mediated central nervous system toxicity'. Together they form a unique fingerprint.

Cite this