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Intrastriatal Methylmalonic Acid Administration Induces Convulsions and TBARS Production, and Alters Na + ,K + ‐ATPase Activity in the Rat Striatum and Cerebral Cortex
Author(s) -
Malfatti Carlos Ricardo Maneck,
Royes Luiz Fernando Freire,
Francescato Leandro,
Sanabria Emílio Rafael Garrido,
Rubin Maribel Antonello,
Cavalheiro Esper Abrão,
Mello Carlos Fernando
Publication year - 2003
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2003.42902.x
Subject(s) - tbars , striatum , chemistry , cerebral cortex , methylmalonic acid , thiobarbituric acid , endocrinology , medicine , biochemistry , lipid peroxidation , dopamine , antioxidant , homocysteine
Summary: Purpose: Methylmalonic acid (MMA) inhibits succinate dehydrogenase (SDH) and β‐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 ∼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.