Succinate causes oxidative damage through N-methyl- d-aspartate-mediated mechanisms

• Published in: Brain research Vol. 1051; no. 1; pp. 66 - 71
• Main Authors: Sinhorin, V.D.G., Roehrs, C., Pasin, J.S.M., Bellé, N.A.V., Rubin, M.A., Mello, C.F.
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 27.07.2005; Amsterdam Elsevier; New York, NY
• Subjects: 3-Nitropropionic acid; Animals; Biochemistry and metabolism; Biological and medical sciences; Central nervous system; Dose-Response Relationship, Drug; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Free radical; Fundamental and applied biological sciences. Psychology; Injections, Intraventricular; Lipid Peroxidation - drug effects; Locomotor behavior; Male; Malonate; Mice; MK-801; Oxidative Stress - drug effects; Oxidative Stress - physiology; Prosencephalon - drug effects; Prosencephalon - metabolism; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Succinate dehydrogenase; Succinic Acid - administration & dosage; Succinic Acid - adverse effects; Thiobarbituric Acid Reactive Substances - analysis; Vertebrates: nervous system and sense organs; Disorders of the nervous system; 3-NPA; DNPH; Succinate dehydrogenase; SDS; fEPSPs; AP5; Malonate; TBARS; MDA; Free radical; MK-801; TBA; ANOVA; SDH; Locomotor behavior; 3-Nitropropionic acid; NMDA; DHBA; ATP; icv; Enzyme; Toxicity; Exploratory behavior; Dizocilpine; Rodentia; Glutamate receptor; Vertebrata; Mammalia; Mouse; Animal; Intracerebral administration; Succinic acid; Oxidoreductases; Antagonist; Behavior; NMDA receptor
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2005.05.053

In this study we investigated whether succinate, the accumulating substrate in succinate dehydrogenase (SDH) deficiencies and SDH inhibitor intoxication, causes lipoperoxidation and protein carbonylation, and if NMDA receptors are involved in the succinate-induced oxidative damage. Adult male mice (30–40 g) received an intracerebroventricular injection of succinic acid (0.7, 1.0 and 1.7 μmol/5 μl) or 0.9% NaCl (5 μl) and had their exploratory behavior assessed in an open field for 10 min. Succinate (0.7 and 1.0 μmol/5 μl) decreased locomotor activity behavior and increased thiobarbituric acid reactive substances (TBARS) and protein carbonylation in the forebrain. Conversely, 1.7 μmol of succinate did not alter locomotor activity or oxidative damage parameters. The involvement of NMDA receptors in the succinate-induced increase of total protein carbonylation content and exploratory behavior inhibition was assessed by co-administrating MK-801 (7 nmol/2.5 μl icv), a noncompetitive NMDA receptor antagonist, with succinate (1 μmol/2.5 μl icv). The co-administration of MK-801 protected against succinate-induced increase of total protein carbonylation and decrease of locomotor activity. These results suggest the involvement of NMDA receptors in these effects of succinate, which may of particular relevance for succinate-accumulating conditions, such as SDH inhibitors intoxication and inherited SDH deficiencies.