Doxorubicin-induced central nervous system toxicity and protection by xanthone derivative of Garcinia mangostana

Neuroscience. 2011 Feb 23;175:292-9. doi: 10.1016/j.neuroscience.2010.11.007. Epub 2010 Nov 11.

Abstract

Doxorubicin (Dox) is a potent, broad-spectrum chemotherapeutic drug used around the world. Despite its effectiveness, it has a wide range of toxic side effects, many of which most likely result from its inherent pro-oxidant activity. It has been reported that Dox has toxic effects on normal tissues, including brain tissue. The present study tested the protective effect of a xanthone derivative of Garcinia Mangostana against Dox-induced neuronal toxicity. Xanthone can prevent Dox from causing mononuclear cells to increase the level of tumor necrosis factor-alpha (TNFα). We show that xanthone given to mice before Dox administration suppresses protein carbonyl, nitrotyrosine and 4-hydroxy-2'-nonenal (4HNE)-adducted proteins in brain tissue. The levels of the pro-apoptotic proteins p53 and Bax and the anti-apoptotic protein Bcl-xL were significantly increased in Dox-treated mice compared with the control group. Consistent with the increase of apoptotic markers, the levels of caspase-3 activity and TUNEL-positive cells were also increased in Dox-treated mice. Pretreatment with xanthone suppressed Dox-induced increases in all indicators of injury tested. Together, the results suggest that xanthone prevents Dox-induced central nervous system toxicity, at least in part, by suppression of Dox-mediated increases in circulating TNFα. Thus, xanthone is a good candidate for prevention of systemic effects resulting from reactive oxygen generating anticancer therapeutics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Brain Chemistry / drug effects
  • Brain Chemistry / physiology
  • Cell Line
  • Disease Models, Animal
  • Doxorubicin / antagonists & inhibitors*
  • Doxorubicin / toxicity*
  • Garcinia mangostana* / chemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / drug therapy
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Neurotoxins / antagonists & inhibitors*
  • Neurotoxins / toxicity*
  • Plant Extracts / pharmacology
  • Plant Extracts / therapeutic use
  • Xanthones / pharmacology*
  • Xanthones / therapeutic use

Substances

  • Antineoplastic Agents, Phytogenic
  • Neuroprotective Agents
  • Neurotoxins
  • Plant Extracts
  • Xanthones
  • Doxorubicin