title: Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutathione depletion.
abstract: The role of mitochondrial energy metabolism in glutamate mediated neurotoxicity was studied in rat neurones in primary culture. A brief (15 min) exposure of the neurones to glutamate caused a dose-dependent (0.01-1 mM) increase in cyclic GMP levels together with delayed (24 h) neurotoxicity and ATP depletion. These effects were prevented by either the nitric oxide (.NO) synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (NAME; 1 mM) or by the N-methyl-D-aspartate (NMDA) glutamate-subtype receptor antagonist D-(-)-2-amino-5-phosphonopentanoate (APV; 0.1 mM). Glutamate exposure (0.1 mM and 1 mM) followed by 24 h of incubation caused the inhibition of succinate-cytochrome c reductase (20-25%) and cytochrome c oxidase (31%) activities in the surviving neurones, without affecting NADH-coenzyme-Q1 reductase activity. The rate of oxygen consumption was impaired in neurones exposed to 1 mM glutamate, either with glucose (by 26%) or succinate (by 39%) as substrates. These effects on the mitochondrial respiratory chain and neuronal respiration, together with the observed glutathione depletion (20%) by glutamate exposure were completely prevented by NAME or APV. Our results suggest that mitochondrial dysfunction and impairment of antioxidant status may account for glutamate-mediated neurotoxicity via a mechanism involving .NO biosynthesis.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Almeida
authors.forename: S J
authors.initials: SJ
authors.lastname: Heales
authors.forename: J P
authors.initials: JP
authors.lastname: Bolaños
authors.forename: J M
authors.initials: JM
authors.lastname: Medina
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009498:Neurotoxins / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D011837:Radiation-Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D019802:Succinic Acid / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011837:Radiation-Protective Agents; D014475:Uncoupling Agents; D012402:Rotenone; C032456:antimycin; D018698:Glutamic Acid; D000968:Antimycin A; D015763:2-Amino-5-phosphonovalerate; D019802:Succinic Acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D005978:Glutathione; D006152:Cyclic GMP; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester