title: Neurotoxicity of glutamate uptake inhibition in vivo: correlation with succinate dehydrogenase activity and prevention by energy substrates.
abstract: Impairment of glutamate uptake or the reverse action of its transporters has been suggested as the mechanism responsible for the increased glutamate extracellular levels associated with ischemic neuronal damage. In previous studies we have shown that glutamate uptake inhibition by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) in the rat striatum and hippocampus in vivo does not induce neuronal death despite the notable increase in the extracellular levels of glutamate and aspartate. However, PDC intracerebral administration leads to neuronal death in rats chronically injected with the mitochondrial toxin 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase (SDH). In the present study we have determined the time course of inhibition of SDH activity in the striatum of rats acutely injected with a single dose of 3-NP (20 mg/kg), and studied its relation to PDC neurotoxicity. PDC induced larger lesions when administered during maximum inhibition of SDH activity while smaller lesions were found when it was injected during recovery of enzyme activity. We also studied the neuroprotective effect of different energy substrates such as creatine, pyruvate, and the ketone bodies beta-hydroxybutyrate and acetoacetate in this experimental model. Our results show partial protection with all compounds except for beta-hydroxybutyrate that showed no protection, while MK-801 completely prevented PDC-induced neuronal damage. We believe that the present results might be of relevance for the understanding of the mechanisms responsible for ischemic neuronal death and its prevention.
authors.affiliation: Instituto de Fisiología Celular, Departamento de Neurociencias, Universidad Nacional Autónoma de México, CP 04510 D.F. AP 70-253, México, Mexico. lmassieu@ifisiol.unam.mx
authors.forename: L
authors.initials: L
authors.lastname: Massieu
authors.forename: P
authors.initials: P
authors.lastname: Del Río
authors.forename: T
authors.initials: T
authors.lastname: Montiel
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000090:Acetoacetates / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000503:physiopathology; D003292:Convulsants / Q000494:pharmacology; D003401:Creatine / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000090:Acetoacetates; D027322:Amino Acid Transport System X-AG; D003292:Convulsants; D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D014179:Neurotransmitter Uptake Inhibitors; D009574:Nitro Compounds; D011422:Propionates; D011759:Pyrrolidines; D018698:Glutamic Acid; D019289:Pyruvic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D013385:Succinate Dehydrogenase; D003401:Creatine; C015392:3-nitropropionic acid; D020155:3-Hydroxybutyric Acid