Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (γ-hydroxybutyric aciduria)

Maneesh Gupta, Rachel Greven, Erwin E W Jansen, Cornelis Jakobs, Boris M. Hogema, Wolfgang Froestl, O. Carter Snead, Hilke Bartels, Markus Grompe, K. Michael Gibson

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

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 GABAB 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.

Original languageEnglish (US)
Pages (from-to)180-187
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume302
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Succinate-Semialdehyde Dehydrogenase
Vigabatrin
Aminobutyrates
Taurine
Benzocycloheptenes
Therapeutics
Brain
4-Aminobutyrate Transaminase
Hydroxybutyrates
Transaminases
Amino Acids
Acids
Survival
succinic semialdehyde dehydrogenase deficiency

ASJC Scopus subject areas

  • Pharmacology

Cite this

Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (γ-hydroxybutyric aciduria). / Gupta, Maneesh; Greven, Rachel; Jansen, Erwin E W; Jakobs, Cornelis; Hogema, Boris M.; Froestl, Wolfgang; Carter Snead, O.; Bartels, Hilke; Grompe, Markus; Michael Gibson, K.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 302, No. 1, 2002, p. 180-187.

Research output: Contribution to journalArticle

Gupta, M, Greven, R, Jansen, EEW, Jakobs, C, Hogema, BM, Froestl, W, Carter Snead, O, Bartels, H, Grompe, M & Michael Gibson, K 2002, 'Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (γ-hydroxybutyric aciduria)', Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 1, pp. 180-187. https://doi.org/10.1124/jpet.302.1.180
Gupta, Maneesh ; Greven, Rachel ; Jansen, Erwin E W ; Jakobs, Cornelis ; Hogema, Boris M. ; Froestl, Wolfgang ; Carter Snead, O. ; Bartels, Hilke ; Grompe, Markus ; Michael Gibson, K. / Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (γ-hydroxybutyric aciduria). In: Journal of Pharmacology and Experimental Therapeutics. 2002 ; Vol. 302, No. 1. pp. 180-187.
@article{c3fc39330b5c44d29481850778835816,
title = "Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (γ-hydroxybutyric aciduria)",
abstract = "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 GABAB 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.",
author = "Maneesh Gupta and Rachel Greven and Jansen, {Erwin E W} and Cornelis Jakobs and Hogema, {Boris M.} and Wolfgang Froestl and {Carter Snead}, O. and Hilke Bartels and Markus Grompe and {Michael Gibson}, K.",
year = "2002",
doi = "10.1124/jpet.302.1.180",
language = "English (US)",
volume = "302",
pages = "180--187",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (γ-hydroxybutyric aciduria)

AU - Gupta, Maneesh

AU - Greven, Rachel

AU - Jansen, Erwin E W

AU - Jakobs, Cornelis

AU - Hogema, Boris M.

AU - Froestl, Wolfgang

AU - Carter Snead, O.

AU - Bartels, Hilke

AU - Grompe, Markus

AU - Michael Gibson, K.

PY - 2002

Y1 - 2002

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 GABAB 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.

AB - 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 GABAB 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.

UR - http://www.scopus.com/inward/record.url?scp=0036085486&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036085486&partnerID=8YFLogxK

U2 - 10.1124/jpet.302.1.180

DO - 10.1124/jpet.302.1.180

M3 - Article

C2 - 12065715

AN - SCOPUS:0036085486

VL - 302

SP - 180

EP - 187

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -