TY - JOUR T1 - Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria) JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 180 LP - 187 DO - 10.1124/jpet.302.1.180 VL - 302 IS - 1 AU - Maneesh Gupta AU - Rachel Greven AU - Erwin E. W. Jansen AU - Cornelis Jakobs AU - Boris M. Hogema AU - Wolfgang Froestl AU - O. Carter Snead AU - Hilke Bartels AU - Markus Grompe AU - K. Michael Gibson Y1 - 2002/07/01 UR - http://jpet.aspetjournals.org/content/302/1/180.abstract N2 - Therapeutic intervention for human succinic semialdehyde dehydrogenase (SSADH) deficiency (γ-hydroxybutyric aciduria) has been limited to vigabatrin (VGB). Pharmacologically, VGB should be highly effective due to 4-aminobutyrate-transaminase (GABA-transaminase) inhibition, lowering succinic semialdehyde and, thereby, γ-hydroxybutyric acid (GHB) levels. Unfortunately, clinical efficacy has been limited. Because GHB possesses a number of potential receptor interactions, we addressed the hypothesis that antagonism of these interactions in mice with SSADH deficiency could lead to the development of novel treatment strategies for human patients. SSADH-deficient mice have significantly elevated tissue GHB levels, are neurologically impaired, and die within 4 weeks postnatally. In the current report, we compared oral versus intraperitoneal administration of VGB, CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid, a GABAB receptor antagonist], and the nonprotein amino acid taurine in rescue of SSADH-deficient mice from early death. In addition, we assessed the efficacy of the specific GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-[H]benzocycloheptene-5-ol-6-ylideneacetic acid) using i.p. administration. All interventions led to significant lifespan extension (22–61%), with NCS-382 being most effective (50–61% survival). To explore the limited human clinical efficacy of VGB, we measured brain GHB and γ-aminobutyric acid (GABA) levels in SSADH-deficient mice receiving VGB. Whereas high-dose VGB led to the expected elevation of brain GABA, we found no parallel decrease in GHB levels. Our data indicate that, at a minimum, GHB and GABABreceptors are involved in the pathophysiology of SSADH deficiency. We conclude that taurine and NCS-382 may have therapeutic relevance in human SSADH deficiency and that the poor clinical efficacy of VGB in this disease may relate to an inability to decrease brain GHB concentrations. The American Society for Pharmacology and Experimental Therapeutics ER -