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

N-Acetylaspartate (NAA) is an important osmolyte in the vertebrate brain th at 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 H-1 magnet ic resonance spectroscopic signal, which has led to its widespread use as a neuronal marker. Utilizing this noninvasive technique, the NAA concentrati ons in normal brain and in brains exhibiting a variety of CNS disease syndr omes 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 re port that the concentration of NAA in brain is malleable and that, in addit ion 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 clas s of NAA-active compounds-pyrazole and pyrazole derivatives-that have the a bility 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 d iscussed.