Therapeutic intervention for human
succinic semialdehyde dehydrogenase (
SSADH) deficiency (
gamma-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,
gamma-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
GABA(B) 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
gamma-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
GABA(B) receptors 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.