In vitro toxicological evaluation of NCS-382, a high-affinity antagonist of γ-hydroxybutyrate (GHB) binding

Vogel, Kara R.; Ainslie, Garrett R.; Roullet, Jean-Baptiste; McConnell, Alice; Gibson, K. Michael

doi:10.1016/j.tiv.2017.01.013

Cited by 5 publications

(15 citation statements)

References 21 publications

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“…A number of gene expression changes correlated between the two animal models. Prkag1 was down-regulated in brain of both models (Vogel et al 2017b; 2017c). Prkag1 is a gamma regulatory subunit of the heterotrimeric AMP-activated protein kinase (AMPK), which also contains an alpha catalytic subunit and a non-catalytic beta subunit (Fig.…”

Section: Future Directionsmentioning

confidence: 92%

“…Accordingly, we employed HLMs and FDA-recommended probe substrates in reactions catalyzed by seven CYP isoforms (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) (Vogel et al 2017b). NCS-382 did not inhibit any of the tested enzymes at the highest tested dose (30 μM).…”

Section: Ncs-382 a Potential Novel Therapeutic For Ssadhdmentioning

confidence: 99%

“…1). Employing VGB, significantly elevated GABA in the CNS can be achieved at relatively low daily doses (~10 mg/kg), or via chronic subcutaneous delivery with calibrated osmotic minipumps (Vogel et al 2016; 2017b). A cardinal difference between these “models” resides in the absence of elevated GHB in VGB-treated aldh5a1 +/+ mice, which enables us to begin to more clearly isolate the role of GABA and its effect on mTOR.…”

Section: Future Directionsmentioning

confidence: 99%

“…The identity of drug metabolizing enzymes active in the biotransformation(s) of NCS-382 also has not been reported, nor has the ability of NCS-382 to inhibit the typical enzymes, namely cytochrome P450s (CYP), involved in the metabolism of drugs. Accordingly, we employed HLMs and FDA-recommended probe substrates in reactions catalyzed by seven CYP isoforms (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) (Vogel et al 2017b). NCS-382 did not inhibit any of the tested enzymes at the highest tested dose (30 μM).…”

Section: Ncs-382 a Potential Novel Therapeutic For Ssadhdmentioning

confidence: 99%

“…HepG2 cells were subsequently used to examine the cellular toxicity of NCS-382 at up to 1 mM. Multiple biomarkers assessing cellular integrity, survival, and organelle function revealed little evidence for NCS-382 cytotoxicity (Vogel et al 2017b). Gene expression studies using NCS-382 in HepG2 cells revealed only a minor number of genes (of 370 tested) showing dysregulation (Table 1).…”

Section: Ncs-382 a Potential Novel Therapeutic For Ssadhdmentioning

confidence: 99%

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Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme‐replacement therapeutic strategies

Vogel

Ainslie

Walters

et al. 2018

J of Inher Metab Disea

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We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived from aldehyde dehydrogenase 5a1 (aldh5a1) mice, the murine model of SSADHD, has highlighted NSC utility as an in vitro system in which to study therapeutics and associated toxicological properties. Gene expression analyses have revealed that transcripts encoding GABA receptors are down-regulated and may remain largely immature in aldh5a1 brain, characterized by excitatory as opposed to inhibitory outputs, the latter being the expected action in the mature central nervous system. This indicates that agents altering chloride channel activity may be therapeutically relevant in SSADHD. The most recent therapeutic prospects include mTOR (mechanistic target of rapamycin) inhibitors, drugs that have received attention with the elucidation of the effects of elevated GABA on autophagy. The outlook for novel therapeutic trials in SSADHD continues to improve.

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Section: Future Directionsmentioning

confidence: 92%

Section: Ncs-382 a Potential Novel Therapeutic For Ssadhdmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Section: Ncs-382 a Potential Novel Therapeutic For Ssadhdmentioning

confidence: 99%

Section: Ncs-382 a Potential Novel Therapeutic For Ssadhdmentioning

confidence: 99%

See 3 more Smart Citations

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme‐replacement therapeutic strategies

Vogel

Ainslie

Walters

et al. 2018

J of Inher Metab Disea

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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

Vogel

Ainslie

McConnell³

et al. 2018

Toxicology in Vitro

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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 (300mg/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 1mM NCS-382 shows minimal evidence of pharmacotoxicity. As well, studies at the molecular level indicate that the effects of NCS-382 at 0.5mM 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.

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Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1–mediated metabolism to the product 4′ hydroxy tangeretin

Surichan

Arroo

Tsatsakis

et al. 2018

Toxicology in Vitro

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In vitro toxicological evaluation of NCS-382, a high-affinity antagonist of γ-hydroxybutyrate (GHB) binding

Cited by 5 publications

References 21 publications

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme‐replacement therapeutic strategies

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme‐replacement therapeutic strategies

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

Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1–mediated metabolism to the product 4′ hydroxy tangeretin

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