title: Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma-hydroxybutyric aciduria).
abstract: 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.
authors.affiliation: Department of Molecular and Medical Genetics and Pediatrics, Oregon Health & Science University, 2525 SW 3rd Avenue, MP-350, Portland, OR 97201, USA.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Gupta
authors.forename: Rachel
authors.initials: R
authors.lastname: Greven
authors.forename: Erwin E W
authors.initials: EE
authors.lastname: Jansen
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Boris M
authors.initials: BM
authors.lastname: Hogema
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Froestl
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
authors.forename: Hilke
authors.initials: H
authors.lastname: Bartels
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D005838:Genotype; D007274:Injections, Intraperitoneal; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010641:Phenotype; D012978:Sodium Oxybate / Q000378:metabolism / Q000652:urine*; D050644:Succinate-Semialdehyde Dehydrogenase; D013534:Survival; D013649:Taste / Q000187:drug effects; D013654:Taurine / Q000494:pharmacology; D020888:Vigabatrin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001567:Benzocycloheptenes; D009943:Organophosphorus Compounds; C066471:NCS 382; D013654:Taurine; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; C066430:CGP 35348; D000445:Aldehyde Oxidoreductases; D050644:Succinate-Semialdehyde Dehydrogenase; D020888:Vigabatrin