Effects of ethanol and of alcohol dehydrogenase inhibitors on the reduction of N-acetylaspartate levels of brain in mice in vivo: a search for substances that may have therapeutic value in the treatment of Canavan disease

Abstract

N-Acetylaspartate (NAA) is an important osmolyte in the vertebrate brain that participates in an intercompartmental metabolic cycle. It is synthesized primarily in neurons from L-aspartate (Asp) and acetyl-CoA and, after its regulated release, it is hydrolysed by aspartoacylase in an oligodendrocyte compartment to produce Asp and acetate. NAA also gives a strong 1H magnetic resonance spectroscopic signal, which has led to its widespread use as a neuronal marker. Utilizing this noninvasive technique, the NAA concentrations in normal brain and in brains exhibiting a variety of CNS disease syndromes have been studied. In normal individuals, the concentration of NAA has been observed to be relatively stable over long periods. However, in many CNS disease processes there are long-term changes in the level of NAA that have been considered to signal changes in neuron density or function. We report that the concentration of NAA in brain is malleable and that, in addition to normal endogenous variation or changes due to disease processes, it can be modified by a variety of exogenous drugs and other substances. As a result of this investigation, we have also been able to identify a new class of NAA-active compounds--pyrazole and pyrazole derivatives--that have the ability to reduce brain NAA concentrations in normal mice. The importance of these findings in understanding the NAA intercompartmental cycle, and its role in Canavan disease, a genetic aspartoacylase deficiency disease, are discussed.