Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

Abstract

Therapeutic intervention for human succinic semialdehyde dehydrogenase (SSADH) deficiency (␥-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, ␥-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 ␥-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.

Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency

“…It may also serve a neuroprotective function, preventing glutamate-induced neuronal excitotoxicity (Chen et al 2001). Taurine has shown benefit in the SSADH-deficient mouse model (Gupta et al 2002).…”

“…Taurine appears effective in the mouse model of SSADH deficiency when administered from birth (Gupta et al 2002). Early therapy may be the key -a "critical period" during which taurine or other interventions might be beneficial.…”

“…This process occurs coincident with weaning of suckling mice, and the observation that taurine is the major constituent of murine breast milk led to an experimental trial and survival benefit (Gupta et al 2002). Taurine (2-aminoethanesulfonic acid) is an abundant free amino acid in various tissues and has important roles in neuromodulation and osmoregulation (Bidri and Choay 2003).…”

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

“…Aldh5a1 −/− mice exhibit developmental delay, ataxia and a seizure disorder that progresses from absence seizures (~post-natal day, P, 15) to lethal status epilepticus (~P25) (Cortez et al, 2004). A variety of pharmacological treatments were attempted to rescue Aldh5a1 −/− mice with limited success (Hogema et al, 2001;Gupta et al, 2002;Cortez et al, 2004). However, it has been reported that pups that continue to suckle beyond weaning age (~P20) live longer than their weanling counterparts, suggesting that the high fat dam's milk may have beneficial effects in this disorder (Hogema et al, 2001).…”

Disorders of GABA, Glycine, Serine and Proline

“…Gamma-hydroxybutyric acid receptor antagonists have been shown to lead to significant lifespan extension in SSD-deficient mice (Gupta et al 2002).…”