PT - JOURNAL ARTICLE AU - Raji Mathew AU - Peethambaran Arun AU - Chikkathur N. Madhavarao AU - John R. Moffett AU - M. A. Aryan Namboodiri TI - Progress toward Acetate Supplementation Therapy for Canavan Disease: Glyceryl Triacetate Administration Increases Acetate, but Not <em>N</em>-Acetylaspartate, Levels in Brain AID - 10.1124/jpet.105.087536 DP - 2005 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 297--303 VI - 315 IP - 1 4099 - http://jpet.aspetjournals.org/content/315/1/297.short 4100 - http://jpet.aspetjournals.org/content/315/1/297.full SO - J Pharmacol Exp Ther2005 Oct 01; 315 AB - Canavan disease (CD) is a fatal genetic neurodegenerative disorder caused by mutations in the gene for aspartoacylase, an enzyme that hydrolyzes N-acetylaspartate (NAA) into l-aspartate and acetate. Because aspartoacylase is localized in oligodendrocytes, and NAA-derived acetate is incorporated into myelin lipids, we hypothesize that an acetate deficiency in oligodendrocytes is responsible for the pathology in CD, and we propose acetate supplementation as a possible therapy. In our preclinical efforts toward this goal, we studied the effectiveness of orally administered glyceryl triacetate (GTA) and calcium acetate for increasing acetate levels in the murine brain. The concentrations of brain acetate and NAA were determined simultaneously after intragastric administration of GTA. We found that the acetate levels in brain were increased in a dose- and time-dependent manner, with a 17-fold increase observed at 1 to 2 h in 20- to 21-day-old mice at a dose of 5.8 g/kg GTA. NAA levels in the brain were not significantly increased under these conditions. Studies using mice at varying stages of development showed that the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age. Also, GTA was significantly more effective as an acetate source than calcium acetate. Chronic administration of GTA up to 25 days of age did not result in any overt pathology in the mice. Based on these results and the current Food and Drug Administration-approved use of GTA as a food additive, we propose that it is a potential candidate for use in acetate supplementation therapy for CD. The American Society for Pharmacology and Experimental Therapeutics