title: Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats.
abstract: Isovaleric acidemia (IVAcidemia) is an inborn error of metabolism due to deficiency of isovaleryl-CoA dehydrogenase activity, leading to predominant accumulation of isovaleric acid (IVA). Patients affected by IVAcidemia suffer from acute episodes of encephalopathy, whose underlying mechanisms are poorly known. In the present study we investigated whether an intracerebroventricular injection of IVA could compromise energy metabolism in cerebral cortex of young rats. IVA administration significantly inhibited (14)CO(2) production from acetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates prepared 24 h after injection. However, no alterations of these parameters were observed 2 h after injection. In contrast, no significant differences were found in the activities of succinate dehydrogenase, isocitrate dehydrogenase, electron transfer chain complexes or creatine kinase in rats sacrificed 2 or 24 h after IVA administration. Moreover, IVA injection significantly inhibited Na(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA administration, while pre-treatment of rats with creatine completely prevented the inhibitory effects of IVA on Na(+),K(+)-ATPase. In conclusion, in vivo administration of IVA inhibits the citric acid cycle probably through the enzyme citrate synthase, as well as Na(+),K(+)-ATPase, a crucial enzyme responsible for maintaining the basal potential membrane necessary for a normal neurotransmission. It is presumed that inhibition of these activities may be involved in the pathophysiology of the neurological dysfunction of isovaleric academic patients. The present findings are of particular interest because treatment with creatine supplementation may represent a potential novel adjuvant therapeutic strategy in IVAcidemia.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil.
authors.forename: César Augusto João
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.forename: Giorgia
authors.initials: G
authors.lastname: de Bortoli
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects / Q000502:physiology; D003401:Creatine / Q000008:administration & dosage*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D045782:Hemiterpenes; D007276:Injections, Intraventricular; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D008845:Microinjections; D010101:Oxygen Consumption; D010421:Pentanoic Acids / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D000085:Acetates; D002250:Carbon Radioisotopes; D045222:Electron Transport Chain Complex Proteins; D045782:Hemiterpenes; D010421:Pentanoic Acids; D002245:Carbon Dioxide; C008216:isovaleric acid; D007521:Isocitrate Dehydrogenase; D013385:Succinate Dehydrogenase; D002950:Citrate (si)-Synthase; D000254:Sodium-Potassium-Exchanging ATPase; D003401:Creatine