title: Intrastriatal methylmalonic acid administration induces convulsions and TBARS production, and alters Na+,K+-ATPase activity in the rat striatum and cerebral cortex.
abstract: OBJECTIVE
  Methylmalonic acid (MMA) inhibits succinate dehydrogenase (SDH) and beta-hydroxybutyrate dehydrogenase activity in vitro. Acute intrastriatal administration of MMA induces convulsions through glutamatergic mechanisms probably involving primary adenosine triphosphate (ATP) depletion and free radical generation. In this study we investigated whether the intrastriatal administration of MMA causes lipoperoxidation and alteration in Na+, K+-ATPase activity ex vivo and characterized the electrographic changes elicited by the intrastriatal administration of this organic acid.
  
  
  METHODS
  MMA-induced lipoperoxidation, alterations in Na+, K+-ATPase activity and electrographic changes were measured by measuring total thiobarbituric acid-reacting substances and inorganic phosphate release by spectrophotometry, and by depth electrode recording, respectively.
  
  
  RESULTS
  We demonstrated that intrastriatal MMA (6 mmol) injection causes convulsive behavior and electrographically recorded convulsions that last approximately 2 h. Concomitant with the increase of thiobarbituric acid-reacting substances (TBARS) content, we observed a significant inhibition of Na+,K+-ATPase activity in the striatum, and activation of Na+,K+-ATPase activity in the ipsilateral cerebral cortex. Intrastriatal MMA injection increased the content of TBARS in the striatum measured 30 min (32.4 +/- 12.0%, compared with the noninjected contralateral striatum) and 3 h (39.7 +/- 5.1%, compared with the noninjected contralateral striatum) after MMA injection. TBARS content of the ipsilateral cerebral cortex increased after MMA injection at 30 min (42.1 +/- 6.0%) and 3 h (40.4 +/- 20.2%), and Na+,K+-ATPase activity in the ipsilateral cerebral cortex increased during ictal activity (113.8 +/- 18%) and returned to basal levels as electrographic convulsions vanished in the cortex. Interestingly, intrastriatal MMA administration induced a persistent decrease in Na+,K+-ATPase activity only in the injected striatum (44.9 +/- 8.1% at 30 min and 68.7 +/- 9.4 at 3 h).
  
  
  CONCLUSIONS
  These data suggest that MMA induces lipoperoxidation associated with Na+,K+-ATPase inhibition or activation, depending on the cerebral structure analyzed. It is suggested that Na+,K+-ATPase inhibition may play a primary role in generating MMA-induced convulsions.
authors.affiliation: Departamento de Química, Universidade Federal de Santa Maria, Brazil.
authors.forename: Carlos Ricardo Maneck
authors.initials: CR
authors.lastname: Malfatti
authors.forename: Luiz Fernando Freire
authors.initials: LF
authors.lastname: Royes
authors.forename: Leandro
authors.initials: L
authors.lastname: Francescato
authors.forename: Emílio Rafael Garrido
authors.initials: ER
authors.lastname: Sanabria
authors.forename: Maribel Antonello
authors.initials: MA
authors.lastname: Rubin
authors.forename: Esper Abrão
authors.initials: EA
authors.lastname: Cavalheiro
authors.forename: Carlos Fernando
authors.initials: CF
authors.lastname: Mello
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008764:Methylmalonic Acid / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism*
chemical_list: D017392:Thiobarbituric Acid Reactive Substances; D008764:Methylmalonic Acid; D000254:Sodium-Potassium-Exchanging ATPase