The effect of N-octyl-ß-valienamine on ß-glucosidase activity in tissues of normal mice.

ABSTRACT

Gaucher disease (GD), mainly caused by a defect of acid ß-glucosidase (ß-Glu), is the most common sphingolipidosis. We have previously shown that a carbohydrate mimic N-octyl-ß-valienamine (NOV), an inhibitor of ß-Glu, could increase the protein level and enzyme activity of various mutant ß-Glu in cultured GD fibroblasts, suggesting that NOV acted as a pharmacological chaperone to accelerate transport and maturation of this mutant enzymes. In the present study, the NOV effect was evaluated for ß-Glu activity, tissue distribution and adverse effects in normal mice. We measured the ß-Glu activity in tissues of normal mice which received water containing increasing concentrations of NOV ad libitum for 1 week. Fluid intake and body weight were measured periodically throughout the study. Measurement of tissue NOV concentration, blood chemistry and urinalysis were performed at the end of the study. The results showed that NOV had no impact on the body weight but fluid intake in the 10mM NOV group mice decreased and there was a moderate increase in blood urea nitrogen (BUN). No other adverse effect was observed during this experiment. Tissue NOV concentration increased in all tissues examined with increasing NOV doses. No inhibitory effect of NOV on ß-Glu was observed. Furthermore, NOV increased the ß-Glu activity in the liver, spleen, muscle and cerebellum of the mice significantly. This study on NOV showed its oral availability and wide tissue distribution, including the brain and its lack of acute toxicity. These characteristics of NOV would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations and selected mutations.