Method development for the determination of 24S‐hydroxycholesterol in human plasma without derivatization by high‐performance liquid chromatography with tandem mass spectrometry in atmospheric pressure chemical ionization mode

Sugimoto, Hiroshi; Kakehi, Masaaki; Satomi, Yoshinori; Kamiguchi, Hidenori; Jinno, Fumihiro

doi:10.1002/jssc.201500719

Cited by 12 publications

(6 citation statements)

References 24 publications

(31 reference statements)

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“…In this study, high-performance liquid chromatography (HPLC)-based assay was employed to improve the throughput of drug discovery campaign instead of LC–MS/MS analysis, which is used for plasma 24 S -hydroxycholesterol analysis in clinical trials 57 . To determine the level of 24 S -hydroxycholesterol in the brain, brain homogenate was prepared as described above.…”

Section: Methodsmentioning

confidence: 99%

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Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Nishi

Kondo

Miyamoto

et al. 2020

Sci Rep

104

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Cholesterol 24-hydroxylase (CH24H) is a brain-specific enzyme that converts cholesterol into 24S-hydroxycholesterol, the primary mechanism of cholesterol catabolism in the brain. The therapeutic potential of CH24H activation has been extensively investigated, whereas the effects of CH24H inhibition remain poorly characterized. In this study, the therapeutic potential of CH24H inhibition was investigated using a newly identified small molecule, soticlestat (TAK-935/OV935). The biodistribution and target engagement of soticlestat was assessed in mice. CH24H-knockout mice showed a substantially lower level of soticlestat distribution in the brain than wild-type controls. Furthermore, brain-slice autoradiography studies demonstrated the absence of [3H]soticlestat staining in CH24H-knockout mice compared with wild-type mice, indicating a specificity of soticlestat binding to CH24H. The pharmacodynamic effects of soticlestat were characterized in a transgenic mouse model carrying mutated human amyloid precursor protein and presenilin 1 (APP/PS1-Tg). These mice, with excitatory/inhibitory imbalance and short life-span, yielded a remarkable survival benefit when bred with CH24H-knockout animals. Soticlestat lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially reduced premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%. Furthermore, microdialysis experiments showed that soticlestat can suppress potassium-evoked extracellular glutamate elevations in the hippocampus. Taken together, these data suggest that soticlestat-mediated inhibition of CH24H may have therapeutic potential for diseases associated with neural hyperexcitation.

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Section: Methodsmentioning

confidence: 99%

“…Measurement of 24S-hydroxycholesterol levels in brain. In this study, high-performance liquid chromatography (HPLC)-based assay was employed to improve the throughput of drug discovery campaign instead of LC-MS/MS analysis, which is used for plasma 24S-hydroxycholesterol analysis in clinical trials 57 .…”

Section: Preparation Of Soticlestatmentioning

confidence: 99%

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Nishi

Kondo

Miyamoto

et al. 2020

Sci Rep

104

View full text Add to dashboard Cite

show abstract

“…The 24S‐HC can be determined either as the free molecule or the total molecule after alkaline hydrolysis of 24S‐HC esters. In addition, the detection can be performed with or without derivatization of the sample (Honda et al., 2009; Bandaru & Haughey, 2014; Sidhu et al., 2015; Sugimoto et al., 2015; Novakova et al., 2015).…”

Section: S‐hc In Brain Diseasesmentioning

confidence: 99%

24S‐hydroxycholesterol: Cellular effects and variations in brain diseases

Sodero

2020

Journal of Neurochemistry

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Cholesterol homeostasis in every tissue is maintained by the delicate mutual regulation between synthesis and catabolism in different cell types. In the mature brain, after myelination has ceased, cholesterol catabolism acquires special relevance to regulate the levels of this lipid, particularly in neurons, because of the general decline of the cholesterol synthesis rate in the brain. The limited synthesis essentially takes place in astrocytes, which have the ability to supply neurons with cholesterol via lipoproptein particles. ATP-binding cassette (ABC) transporters on the astrocyte's plasma membrane are in charge of exporting the synthetized cholesterol to the extracellular milieu. The brain apolipoproteins needed to assemble the lipoprotein particles (ApoE and ApoJ) are also produced and secreted by astrocytes. Ultimately, the lipoprotein particles that carry cholesterol are internalized into neurons after the interaction with surface lipoprotein receptors of the LRP and LDL families (Vitali et al., 2014; Zhang & Liu, 2015) (see Figure 1).Cholesterol synthesis in the brain involves the same molecular reactions than in the liver, being the initial precursor acetyl-CoA.The major regulatory check-point of the cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate by the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a known target of the statins. The transcription of this enzyme is controlled by sterol regulatory element-binding proteins (SREBPs), transcription factors that can bind an sterol-regulatory element (SRE) in the promoter region of the HMGCR gene. The SREBP family is integrated by three isoforms: SREBP-1a, SREBP-1c, and SREBP-2. Among them SREBP-2 is the most abundant in brain tissue (Camargo et al.,

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“…A 100 μL aliquot of human plasma (or serum) was taken from the stability tests or clinical studies and mixed with 10 μL of 4β-HC-d7 (internal standard, 1 μg/mL in 2-propanol), 50 μL of BHT (antioxidant, 1 mg/mL in ethanol), 350 μL of Tween 80 (1% in phosphate-buffered saline (PBS)), and 1 mL of sodium methoxide (2 mol/L in methanol/ethanol (2:3, v / v )) [ 20 , 31 ]. Each sample was saponified at room temperature for 20 min, mixed with 4 mL of hexane and 500 μL of saturated NaCl solution, and held at room temperature for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Clinical Evaluation Based on a New Approach to Improve the Accuracy of 4β-Hydroxycholesterol Measurement as a Biomarker of CYP3A4 Activity

et al. 2023

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This study examines 4β-Hydroxycholesterol (4β-HC), which is considered to be a potential marker for the CYP3A4 induction of new chemical entities (NCEs) in drug development. To ensure the use of 4β-HC as a practical biomarker, it is necessary to accurately measure 4β-HC and demonstrate that CYP3A4 induction can be appropriately assessed, even for weak inducers. In clinical trials of NCEs, plasma is often collected with various anticoagulants, in some cases, the plasma is acidified, then stored for an extended period. In this study, we examined the effects of these manipulations on the measurement of 4β-HC, and based on the results, we optimized the plasma collection and storage protocols. We also found that a cholesterol oxidation product is formed when plasma is stored, and by monitoring the compound, we were able to identify when plasma was stored inappropriately. After evaluating the above, clinical drug–drug interaction (DDI) studies were conducted using two NCEs (novel retinoid-related orphan receptor γ antagonists). The weak CYP3A4 induction by the NCEs (which were determined based on a slight decline in the systemic exposure of a probe substrate (midazolam)), was detected by the significant increase in 4β-HC levels (more specifically, 4β-HC/total cholesterol ratios). Our new approach, based on monitoring a cholesterol oxidation product to identify plasma that is stored inappropriately, allowed for the accurate measurement of 4β-HC, and thus, it enabled the evaluation of weak CYP3A4 inducers in clinical studies without using a probe substrate.

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Method development for the determination of 24S‐hydroxycholesterol in human plasma without derivatization by high‐performance liquid chromatography with tandem mass spectrometry in atmospheric pressure chemical ionization mode

Cited by 12 publications

References 24 publications

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice

24S‐hydroxycholesterol: Cellular effects and variations in brain diseases

Clinical Evaluation Based on a New Approach to Improve the Accuracy of 4β-Hydroxycholesterol Measurement as a Biomarker of CYP3A4 Activity

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