Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency

• Published in: Brain research 2004-12, Vol.1030 (1), p.141-151
• Main Authors: Reis de Assis, Dênis, Maria, Rita de Cássia, Borba Rosa, Rafael, Schuck, Patrícia Fernanda, Ribeiro, César Augusto João, da Costa Ferreira, Gustavo, Dutra-Filho, Carlos Severo, Terezinha de Souza Wyse, Angela, Duval Wannmacher, Clóvis Milton, Santos Perry, Marcos Luiz, Wajner, Moacir
• Format: Article
• Language: English
• Subjects: Acetates - metabolism; Acyl-CoA Dehydrogenase - deficiency; Age Factors; Animals; Antifungal Agents - pharmacology; Antihypertensive Agents - pharmacology; Biochemistry and metabolism; Biological and medical sciences; Caprylates - pharmacology; Carbon Radioisotopes; Central nervous system; Cerebral Cortex - metabolism; cis-4-decenoic acid; Citrate (si)-Synthase - metabolism; Creatine Kinase - metabolism; Decanoic acid; Decanoic Acids - pharmacology; Electron Transport - physiology; Energy metabolism; Energy Metabolism - drug effects; Energy Metabolism - physiology; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Lipid Metabolism, Inborn Errors - metabolism; Medium-chain acyl-coenzyme A dehydrogenase deficiency; Octanoic acid; Rats; Rats, Wistar; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.10.010

Patients affected by medium-chain acyl CoA dehydrogenase (MCAD) deficiency, a frequent inborn error of metabolism, suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. In the present study, we investigated the in vitro effect of the medium-chain fatty acids (MCFA), at concentrations varying from 0.01 to 3 mM, accumulating in MCAD deficiency on some parameters of energy metabolism in cerebral cortex of young rats. 14CO 2 production from [U 14] glucose, [1- 14C] acetate and [1,5- 14C] citrate was evaluated by incubating cerebral cortex homogenates from 30-day-old rats in the absence (controls) or presence of octanoic acid, decanoic acid or cis-4-decenoic acid. OA and DA significantly reduced 14CO 2 production from acetate by around 30–40%, and from glucose by around 70%. DA significantly reduced 14CO 2 production from citrate by around 40%, while OA did not affect this parameter. cDA inhibited 14CO 2 production from all tested substrates by around 30–40%. The activities of the respiratory chain complexes and of creatine kinase were also tested in the presence of DA and cDA. Both metabolites significantly inhibited cytochrome c oxidase activity (by 30%) and complex II–III activity (DA, 25%; cDA, 80%). Furthermore, only cDA inhibited complex II activity (by 30%), while complex I–III and citrate synthase were not affected by these MCFA. On the other hand, only cDA reduced the activity of creatine kinase in total homogenates, as well as in mitochondrial and cytosolic fractions from cerebral cortex (by 50%). The data suggest that the major metabolites which accumulate in MCAD deficiency, with particular emphasis to cDA, compromise brain energy metabolism. We presume that these findings may contribute to the understanding of the pathophysiology of the neurological dysfunction of MCAD deficient patients.