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Brain mitochondrial DNA damage and lipid peroxidation induced by kainic acid in vitro: Role of the Krebs cycle
Author(s) -
Yamamoto Hiroaki
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1133-c
Subject(s) - citrate synthase , citric acid cycle , kainic acid , lipid peroxidation , biochemistry , aconitase , incubation , malate dehydrogenase , succinate dehydrogenase , chemistry , glycolysis , malonate , biology , enzyme , glutamate receptor , receptor
The homogenate of mice brain incubated with different concentrations of kainic acid (0, 0.05, 0.5 or 1.0 mM) or 2‐methylcitrate (1.0 or 5.0 mM), an inhibitor of enzymes such as citrate synthase, aconitase and isocitrate dehydrogenase on the Krebs cycle, at 37 degrees centigrade for 60 min was elicited damage to brain mitochondrial DNA (mtDNA) in a concentration dependent manner. 1.0 mM kainic acid‐induced brain mtDNA damage was completely abolished by co‐incubation of oxaloacetate (5.0mM), α‐ketoglutarate (5.0mM), citrate (5.0 mM), succinate (5.0 mM), malate (5.0 mM), fumarate (5.0 mM) but not by co‐incubation of maleate (5.0 mM) or malonate (5.0 mM). Furthermore, preventive effects of oxaloacetate, α‐ketoglutarate or citrate against kainic acid‐induced DNA damage were a concentration dependent. However, 1.0 mM 2‐methylcitrate‐induced brain mtDNA damage was not prevented by co‐incubation of citrate (5.0 mM). The in vitro exposure of mice brain homogenates to kainic acid (0.1 or 1.0 mM) or 2‐methylcitrate (1.0 or 5.0 mM) caused a significant increase in the concentration of malonaldehyde (MDA) and 4‐hydroxyalkenals (4‐HDA) (compared to control samples) in a concentration‐dependent manner. The increased lipid peroxidation induced by kainic acid was attenuated by co‐incubation with substrates of enzymes in the Krebs cycle such as α‐ketoglutarate (5.0 mM), oxaloacetate (5.0 mM), citrate (5.0 mM), succinate (5.0 mM), malate (5.0 mM) and fumarate (5.0 mM) but not maleate (5.0 mM) or malonate (5.0 mM). The increased lipid peroxidation induced by 2‐methylcitrate was not attenuated by co‐incubation of citrate (5.0 mM). These results suggest that there may be a negative relationship between kainic acid‐induced brain mtDNA damage and stimulation of the Krebs cycles.