Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells

Therapeutic implications for SSADH deficiency, a GABA metabolic disorder

K. R. Vogel, G. R. Ainslie, A. McConnell, Jean-Baptiste Roullet, K. M. Gibson

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

We report the in vitro assessment of pharmacotoxicity for the high-affinity GHB receptor ligand, NCS-382, using neuronal stem cells derived from mice with a targeted deletion of the aldehyde dehydrogenase 5a1 gene (succinic semialdehyde dehydrogenase(SSADH)-deficient mice). These animals represent a phenocopy of the human disorder of GABA metabolism, SSADH deficiency, that metabolically features accumulation of both GABA and the GABA-analog γ-hydroxybutyric acid in conjunction with a nonspecific neurological phenotype. We demonstrate for the first time using MDCK cells that NCS-382 is actively transported and capable of inhibiting GHB transport. Following these in vitro assays with in vivo studies in aldh5a1−/− mice, we found the ratio of brain/liver GHB to be unaffected by chronic NCS-382 administration (300 mg/kg; 7 consecutive days). Employing a variety of cellular parameters (reactive oxygen and superoxide species, ATP production and decay, mitochondrial and lysosomal number, cellular viability and necrosis), we demonstrate that up to 1 mM NCS-382 shows minimal evidence of pharmacotoxicity. As well, studies at the molecular level indicate that the effects of NCS-382 at 0.5 mM are minimally toxic as evaluated using gene expression assay. The cumulative data provides increasing confidence that NCS-382 could eventually be considered in the therapeutic armament for heritable SSADH deficiency.

Original languageEnglish (US)
Pages (from-to)203-212
Number of pages10
JournalToxicology in Vitro
Volume46
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Fingerprint

Succinate-Semialdehyde Dehydrogenase
Hydroxybutyrates
Transport properties
gamma-Aminobutyric Acid
Epithelial Cells
Ligands
Assays
Therapeutics
Aldehyde Dehydrogenase
Madin Darby Canine Kidney Cells
Poisons
Stem cells
Metabolism
Gene expression
Superoxides
Liver
NCS 382
succinic semialdehyde dehydrogenase deficiency
Reactive Oxygen Species
Brain

Keywords

  • GABA metabolism
  • NCS-382
  • Neuronal stem cells
  • SSADH deficiency (SSADHD)
  • Succinic semialdehyde dehydrogenase (SSADH)
  • γ-Hydroxybutyric acid (GHB)

ASJC Scopus subject areas

  • Toxicology

Cite this

Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells : Therapeutic implications for SSADH deficiency, a GABA metabolic disorder. / Vogel, K. R.; Ainslie, G. R.; McConnell, A.; Roullet, Jean-Baptiste; Gibson, K. M.

In: Toxicology in Vitro, Vol. 46, 01.02.2018, p. 203-212.

Research output: Contribution to journalArticle

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