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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
| Content Provider | Scilit |
|---|---|
| Author | Vogel, K. R. Ainslie, G. R. McConnell, A. Roullet, J. -B. Gibson, K. M. |
| Copyright Year | 2017 |
| Description | Journal: Toxicology in Vitro 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842807/pdf |
| Ending Page | 212 |
| Page Count | 10 |
| Starting Page | 203 |
| ISSN | 08872333 |
| e-ISSN | 18793177 |
| DOI | 10.1016/j.tiv.2017.10.015 |
| Journal | Toxicology in Vitro |
| Volume Number | 46 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2017-10-12 |
| Access Restriction | Open |
| Subject Keyword | Journal: Toxicology in Vitro Biochemistry and Molecular Biology Succinic Semialdehyde Dehydrogenase (ssadh) Ssadh Deficiency (ssadhd) Γ-hydroxybutyric Acid (ghb) Neuronal Stem Cells |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology |
