Isovaleric Acid Reduces Na super(+), K super(+)-ATPase Activity in Synaptic Membranes from Cerebral Cortex of Young Rats

• Published in: Cellular and molecular neurobiology Vol. 27; no. 4; pp. 529 - 540
• Main Authors: Ribeiro, Cesar AJ, Balestro, Fabricio, Grando, Vanessa, Wajner, Moacir
• Format: Journal Article
• Language: English
• Published: 01.06.2007
• ISSN: 0272-4340
• DOI: 10.1007/s10571-007-9143-3

1. Patients affected by isovaleric acidemia (IVAcidemia) suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. The objective of the present study was to investigate the in vitro effects of the metabolites that predominantly accumulate in IVAcidemia, namely isovaleric acid (IVA), 3-hydroxyisovaleric acid (3-OHIVA) and isovalerylglycine (IVG), on important parameters of energy metabolism, such as super(14)CO sub(2) production from acetate and the activities of the respiratory chain complexes I-IV, creatine kinase and Na super(+), K super(+)-ATPase in synaptic plasma membranes from cerebral cortex homogenates of 30-day-old rats.2. We observed that 3-OHIVA acid and IVG did not affect all the parameters analyzed. Similarly, super(14)CO sub(2) production from acetate (Krebs cycle activity), the activities of creatine kinase, and of the respiratory chain complexes was not modified by IVA. In contrast, IVA exposition to cortical homogenates provoked a marked inhibition of Na super(+), K super(+)-ATPase activity. However, this activity was not changed when IVA was directly exposed to purified synaptic plasma membranes, suggesting an indirect effect of this organic acid on the enzyme. Furthermore, pretreatment of cortical homogenates with alpha -tocopherol and creatine totally prevented IVA-induced inhibition on Na super(+), K super(+)-ATPase activity from synaptic plasma membranes, whereas glutathione (GSH) and the NO synthase inhibitor N super( omega )-nitro-l-arginine methyl ester (L-NAME) did not alter this inhibition.3. These data indicate that peroxide radicals were probably involved in this inhibitory effect. Since Na super(+), K super(+)-ATPase is a critical enzyme for normal brain development and functioning and necessary to maintain neuronal excitability, it is presumed that the inhibitory effect of IVA on this activity may be involved in the pathophysiology of the neurological dysfunction of isovaleric acidemic patients.