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

5 Scopus citations

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

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Keywords

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

ASJC Scopus subject areas

  • Toxicology

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