Intrastriatal methylmalonic acid administration induces convulsions and TBARS production, and alters Na+,K+-ATPase activity in the rat striatum and cerebral cortex.
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.
Malfatti
Carlos Ricardo Maneck
CR
Departamento de Química, Universidade Federal de Santa Maria, Brazil.
Royes
Luiz Fernando Freire
LF
Francescato
Leandro
L
Sanabria
Emílio Rafael Garrido
ER
Rubin
Maribel Antonello
MA
Cavalheiro
Esper Abrão
EA
Mello
Carlos Fernando
CF
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*
D017392:Thiobarbituric Acid Reactive Substances; D008764:Methylmalonic Acid; D000254:Sodium-Potassium-Exchanging ATPase