Aim: To examine whether liquiritigenin, a newly found agonist of selective estrogen receptor-β, has neuroprotective activity against β-amyloid peptide (Aβ) in rat hippocampal neurons. Methods: Primary cultures of rat hippocampal neurons were pretreated with liquiritigenin (0.02, 0.2, and 2 pmol/L) prior to Aβ25-35 exposure. Following treatment, viability of the cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis and by a lactate dehydrogenase activity-based cytotoxicity assay. Intracellular Ca^2+ concentration ([Ca^2+]i) and levels of reactive oxygen species (ROS), as well as apoptotic rates, were determined. Our studies were extended in tests of whether liquiritigenin treatment could inhibit the secretion of Aβ1-40 as measured using an ELISA method. In order to analyze which genes may be involved, we used a microarray assay to compare gene expression patterns. Finally, the levels of specific proteins related to neurotrophy and neurodenegeration were detected by Western blotting. Results: Pretreated neurons with liquiritigenin in the presence of Aβ25-35 increased cell viability in a concentration-dependent manner. Liquiritigenin treatment also attenuated Aβ25-35-induced increases in [Ca^2+]i and ROS level and decreased the apoptotic rate of neurons. Some genes, including B-cell lymphoma/leukemia-2 (Bcl-2), neurotrophin 3 (Ntf-3) and amyloid [3 (A4) precursor protein-binding, family B, member 1 (Apbb-1) were regulated by liquiritigenin; similar results were shown at the protein level by Western blotting. Conclusion: Our results demonstrate that liquiritigenin exhibits neuroprotective effects against Aβ25-35-induced neurotoxicity and that it can decrease the secretion of Aβ1-40. Therefore, liquiritigenin may be useful for further study as a prodrug for treatment of Alzheimer's disease. 相似文献
Isoliquiritigenin (ILQ), a flavonoid compound originated from Glycyrrhiza species, is known to activate SIRT1. Arachidonic acid (AA) in combination with iron (a catalyst of auto-oxidation) leads cells to produce excess reactive species with a change in mitochondrial permeability transition. In view of the importance of oxidative stress in cell death and inflammation, this study investigated the potential of ILQ to protect cells against the mitochondrial impairment induced by AA + iron and the underlying basis for this cytoprotection. Treatment with ILQ inhibited apoptosis induced by AA + iron, as evidenced by alterations in the levels of the proteins associated with cell viability: ILQ prevented a decrease in Bcl-xL, and cleavage of poly(ADP-ribose)polymerase and procaspase-3. Moreover, ILQ inhibited the ability of AA + iron to elicit mitochondrial dysfunction. In addition, superoxide generation in mitochondria was attenuated by ILQ treatment. Consistently, ILQ prevented cellular H2O2 production increased by AA + iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β), and prevented a decrease in the GSK3β phosphorylation elicited by AA + iron, which contributed to protecting cells and mitochondria. GSK3β phosphorylation by ILQ was preceded by AMP-activated protein kinase (AMPK) activation, which was also responsible for mitochondrial protection, as shown by reversal of its effect in the experiments using a dominant negative mutant of AMPK and compound C. Moreover, the AMPK activation led to GSK3β phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA + iron-induced H2O2 production and mitochondrial dysfunction, which is mediated with GSK3β phosphorylation downstream of AMPK. 相似文献
Cytoprotective effects of liquiritigenin (LQ) against liver injuries have been reported, but its pharmacokinetics has not been studied in acute hepatitis. Thus, pharmacokinetics of LQ and its two conjugated glucuronide metabolites: 4′-O-glucuronide (M1) and 7-O-glucuronide (M2), in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide (GalN/LPS) rats or carbon tetrachloride-treated (CCl4-treated) rats were evaluated.
LQ was administered intravenously (20?mg kg?1) and orally (50?mg kg?1) to control GalN/LPS and CCl4-treated rats. Expression of uridine 5′-diphospho-glucuronosyltransferases 1A (UGT1A) and in vitro metabolism of LQ in hepatic and intestinal microsomes were also measured.
After intravenous administration of LQ, area under the plasma concentration-time curve (AUC) of LQ in GalN/LPS rats was significantly smaller than that in controls due to faster non-renal clearance, as a result of its greater free fraction in plasma and faster hepatic blood flow rate than the controls. In CCl4-treated rats, the AUCM1, 0?8 h/AUCLQ and AUCM2, 0?8 h/AUCLQ ratios were significantly greater than the controls due to decrease in biliary excretion of M1 and M2. However, no significant pharmacokinetic changes were observed in both acute hepatitis rats after oral administration due to comparable intestinal metabolism of LQ.
Modification of oral dosage regimen of LQ may not be necessary in patients with acute hepatitis; but human studies are required.