Abstract
Recently, potent neuroprotective and anti-diabetic effects of 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid isolated from Tussilago farfara Linnaeus, have been elucidated. To facilitate further pre-clinical evaluation in rats, an analytical method for the determination of ECN in rat plasma was developed and optimized by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma samples were pretreated by the protein precipitation method with an acetonitrile solution of losartan (LST) as the internal standard. Chromatographic separation was performed using a an Octadecyl-silica (ODS) column (2.6 µm, 100 x 4.6 mm) in the isocratic mode. The mobile phase, comprising 10 mM ammonium formate in water pH 5.75) and acetonitrile (11:89, v/v), was eluted at a flow rate of 0.4 mL/min. Mass spectrometric detection was performed in the multiple reaction monitoring mode with positive electrospray ionization, and the mass transitions of ECN and LST were m/z 431.3 to 97.3 and m/z 423.1 to 207.2, respectively. The calibration curves of spiked plasma samples were linear in the 10.0–10,000 ng/mL range (r2 > 0.996). The lower limit of quantification (LLOQ) was determined as 10.0 ng/mL. Validation was conducted in the LLOQ, and three quality control (QC) sample levels (10.0, 25.0, 3750, and 7500 ng/mL) were studied. Among them, the relative standard deviation for the within- and between-run precisions was under 9.90%, and the relative error of the accuracies was within the −8.13% to 0.42% range. The validated method was successfully employed to investigate the pharmacokinetic properties of ECN in rats, which revealed the linear pharmacokinetic behavior of ECN for the first time.
Highlights
Tussilago farfara Linnaeus (Asteraceae) is a perennial herbaceous plant, which is widespread acrossEast Asia, North Africa, Siberia, and Europe, and contains various active compounds that can alleviateMolecules 2020, 25, 1774; doi:10.3390/molecules25081774 www.mdpi.com/journal/moleculesMolecules 2020, 25, 1774 several disease-related symptoms [1,2,3]
The results indicated that both analytes exhibited higher intensity during mass scanning in the electrospray ionization (ESI) positive mode than in the negative mode, where protonated molecular ions were dominantly observed with an m/z of 431.3 for ECN and an m/z of 423.1 for LST
These [M+H]+ ions were selected as the precursor ions, which were fragmented using the product ion scan mode to single out daughter ions for further analysis in the multiple reaction monitoring (MRM) mode
Summary
Tussilago farfara Linnaeus (Asteraceae) is a perennial herbaceous plant, which is widespread acrossEast Asia, North Africa, Siberia, and Europe, and contains various active compounds that can alleviateMolecules 2020, 25, 1774; doi:10.3390/molecules25081774 www.mdpi.com/journal/moleculesMolecules 2020, 25, 1774 several disease-related symptoms [1,2,3]. The sesquiterpenoids, terpenoids, steroids, and flavonoids isolated from Tussilago are well known for their antioxidant [4], anti-inflammatory [5,6,7], anti-microbial [8], anti-tuberculosis [9], anti-tussive [10,11], anti-α-glucosidase [12], anti-platelet [13], anti-cancer [14], and neuroprotection effects [15]. Some terpenoids isolated from this plant displayed cellular protection activities against various oxidative stresses and xenobiotic damages [16,17]. -3,14-dehydro-Z-notonipetranone (ECN) displayed cytoprotection effects in microglial cells, by inhibition of nitric oxide, prostaglandin E2, and tumor necrosis factor-α productions via nuclear factor- κB (NF-κB) pathway suppression [18]. ECN displayed inhibition of diacylglycerol acyltransferase (DGAT1) activity, which suggests its potential therapeutic application for the treatment of obesity and type II diabetes [20]
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