The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Involvement of Oxidative Stress and Poly(ADP-ribose) Polymerase Activation in 3-Nitropropionic Acid-induced Cytotoxicity in Human Neuroblastoma Cells

  • Nam, Eun-Joo (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center) ;
  • Lee, Young-Jae (Maria Infertility Hospital, Biomedical Research Institute) ;
  • Oh, Young-Ah (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center) ;
  • Jung, Jin-Ah (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center) ;
  • Im, Hye-In (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center) ;
  • Koh, Seong-Eun (Department of Rehabilitation Medicine, Konkuk University College of Medicine) ;
  • Maeng, Sung-Ho (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center) ;
  • Joo, Wan-Seok (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center) ;
  • Kim, Yong-Sik (Department of Pharmacology, Seoul National University College of Medicine and Neuroscience Research Institute, Medical Research Center)
  • Published : 2003.12.21
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Abstract

3-Nitropropionic acid (3-NP) inhibits electron transport in mitochondria, leading to a metabolic failure. In order to elucidate the mechanism underlying this toxicity, we examined a few biochemical changes possibly involved in the process, such as metabolic inhibition, generation of reactive oxygen species (ROS), DNA strand breakage, and activation of Poly(ADP-ribose) polymerase (PARP). Exposure of SK-N-BE(2)C neuroblastoma cells to 3-NP for 48 h caused actual cell death, while inhibition of mitochondrial function was readily observed when exposed for 24 h to low concentrations (0.2${\sim}$2 mM) of 3-NP. The earliest biochemical change detected with low concentration of 3-NP was an accumulation of ROS (4 h after 3-NP exposure) followed by degradation of DNA. PARP activation by damaged DNA was also detectable, but at a later time. The accumulation of ROS and DNA strand breakage were suppressed by the addition of glutathione or N-acetyl-L-cysteine (NAC), which also partially restored mitochondrial function and cell viability. In addition, inhibition of PARP also reduced the 3-NP-induced DNA strand breakage and cytotoxicity. These results suggest that oxidative stress and activation of PARP are the major factors in 3-NP-induced cytotoxicity, and that the inhibition of these factors may be useful in protecting neuroblastoma cells from 3-NP-induced toxicity.

Keywords

References

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