Evaluation of the mechanism underlying the inhibitory effect of guanidinoacetate on brain Na+, K+-ATPase activity.

Abstract

Guanidinoacetate methyltransferase deficiency (GAMT-deficiency) is an inherited neurometabolic disorder clinically characterized by epilepsy and mental retardation and biochemically by accumulation of guanidinoacetate (GAA) and depletion of creatine. Although the neurological symptoms are predominant, the pathogenesis of the brain dysfunction in this disorder is not yet established. In the present study we investigated the in vitro effect of GAA on Na+, K+-ATPase and Mg2+-ATPase activities in synaptic plasma membrane from hippocampus of young rats. Results showed that GAA significantly inhibited Na+, K+-ATPase activity without affecting Mg2+-ATPase activity. We also evaluated the effect of glutathione (GSH), trolox, Nomega-nitro-L-arginine methyl ester (L-NAME) and taurine (Tau) on the inhibition elicited by GAA on Na+, K+-ATPase activity. GSH, trolox, L-NAME and Tau per se did not alter Na+, K+-ATPase activity. However, L-NAME and taurine prevented the inhibitory effect of GAA on this enzyme activity. Our findings suggest that the inhibition of Na+, K+-ATPase activity caused by GAA is possibly mediated by nitric oxide (NO) formation and/or synaptic membrane alteration. The present data may contribute to the understanding of the neurological dysfunction characteristic of GAMT-deficient patients.

• Authors: Alexandra I Zugno, Renata Franzon, Fábria Chiarani, Caren S Bavaresco, Clovis M D Wannmacher, Moacir Wajner, Angela T S Wyse
• Journal: International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience (Int J Dev Neurosci) Vol. 22 Issue 4 Pg. 191-6 (Jun 2004) ISSN: 0736-5748 [Print] United States
• PMID: 15245754 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Chromans
• Enzyme Inhibitors
• Thiobarbituric Acid Reactive Substances
• tau Proteins
• Gamt protein, rat
• Guanidinoacetate N-Methyltransferase
• Ca(2+) Mg(2+)-ATPase
• Sodium-Potassium-Exchanging ATPase
• Glutathione
• glycocyamine
• 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
• Glycine
• NG-Nitroarginine Methyl Ester

Topics

• Analysis of Variance
• Animals
• Antioxidants (pharmacology)
• Ca(2+) Mg(2+)-ATPase (metabolism)
• Chromans (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Glutathione (pharmacology)
• Glycine (analogs & derivatives, pharmacology)
• Guanidinoacetate N-Methyltransferase
• Hippocampus (drug effects, metabolism)
• In Vitro Techniques
• NG-Nitroarginine Methyl Ester (pharmacology)
• Rats
• Rats, Wistar
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Synaptic Membranes (drug effects, physiology)
• Thiobarbituric Acid Reactive Substances (metabolism)
• tau Proteins (pharmacology)