Xanthine oxidase-induced neuronal death via the oxidation of NADH: prevention by micromolar EDTA.
The oxidation of xanthine by xanthine oxidase (XO) or xanthine dehydrogenase represents an important source of reactive oxygen species (ROS), which contribute to the damaging consequences of cerebral ischemia, inflammation, and neurodegenerative disorders. However, both enzymes are also able to act on reduced nicotinamide adenine dinucleotide (NADH). The FAD binding site to which NADH binds is distinct from that of the xanthine binding site. We report that the combination of xanthine oxidase and NADH is toxic to cultures of cerebellar granule neurons. Protection by superoxide dismutase (Cu,Zn-SOD or Mn-SOD) or catalase indicates mediation of the toxicity by superoxide and hydrogen peroxide. In addition, pre-incubating XO with EDTA at concentrations as low as 2 microM, prevented the toxicity, indicating that a metal contaminating XO is involved in producing the toxic effects of XO/NADH. It is possible that such a metal might play a role in the toxicity of XO in vivo.
Al-Gonaiah
Majed
M
Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK.
Smith
Robert A
RA
Stone
Trevor W
TW
D000818:Animals; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology; D004492:Edetic Acid / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008670:Metals / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000633:toxicity*
D008670:Metals; D018696:Neuroprotective Agents; D009243:NAD; D009569:Nitric Oxide; D004492:Edetic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase