Tacrine, an Oral Acetylcholinesterase Inhibitor, Induced Hepatic Oxidative Damage, Which Was Blocked by Liquiritigenin through GSK3-beta Inhibition

Abstract

Although the cholinesterase inhibitor tacrine has been successfully used for the treatment of Alzheimer's disease, it is known to have hepatotoxic effects. Liquiritigenin (LQ), an active flavonoid in Glycyrrhizae radix, exerts protective effects against liver damage. This study investigated the toxic effect of tacrine on hepatocytes and the beneficial effect of LQ on tacrine intoxication in vivo and in vitro, and the underlying mechanism involved. In hepatocyte cell lines, tacrine induced cell death and oxidative stress, as indicated by decreases in cell viability and glutathione (GSH) contents, which were blocked by pretreatment with LQ. Fluorescent activated cell sorter (FACS) analysis revealed that LQ inhibited cellular H 2 O 2 production and mitochondrial dysfunction induced by tacrine in HepG2 cells. Furthermore, LQ promoted inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) and prevented decreases in GSK3β phosphorylation induced by tacrine. In rats treatment with tacrine at 30 mg/kg increased hepatic damage as assessed by blood biochemistry and histopathology. Administration of LQ (10 or 30 mg/kg/d, per os (p.o.)) or the hepatoprotective drug sylimarin (100 mg/kg/d) for 3 d inhibited elevations in alanine aminotransferase, aspartate aminotransferase, and histological changes induced by tacrine. These results show that LQ efficaciously protects the rat liver against tacrine-induced liver damage, and suggest that LQ is a therapeutic candidate for ameliorating the hepatotoxic effects of tacrine.Key words tacrine; liquiritigenin; glycogen synthase kinase-3β; liver; oxidative stress; mitochondria Tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) is recommended as the first-line treatment for Alzheimer's disease by the US Food and Drug Administration. It is an active cholinesterase inhibitor that blocks the degradation of cholinergic nerves in the cerebral cortex and hippocampus to increase cholinergic transmission. 1) However, although tacrine has positive therapeutic effects, it has been demonstrated to increased serum alanine aminotransferase (ALT) levels in about 30% of patients, and this seriously limits its clinical use.2) A number of authors have reported that tacrine-induced hepatotoxicity is related to cytochrome P450 1A2 in human liver microsomes and is associated with mitochondrial dysfunction.3-5) Studies also have showed that the hepatotoxic effect of tacrine is associated with oxidative stress, as demonstrated by increased reactive oxygen species (ROS) production and decreased intracellular glutathione (GSH).6-8) However, mechanism responsible for tacrine-induced hepatotoxicity has not yet been elucidated. Nevertheless many studies have shown that anthraquinones, chromone glycosides, phenolic amide, and an herbal medicine protect hepatocytes from the toxic effects of tacrine. [9][10][11][12] Oxidative stress is state in which the balance between ROS production and antioxidants is shifted in favor of ROS, and is associated with severity of liver damage.13) ROS normally work ...

Protective Effects of Liquiritigenin against Citrinin-Triggered, Oxidative-Stress-Mediated Apoptosis and Disruption of Embryonic Development in Mouse Blastocysts

“…However, the average fetal weight of 10 μM CTN-treated groups was lower than that of the untreated control group ( Figure 3 C). Earlier studies suggest that fetal weight is an important indicator of developmental status [ 20 , 29 , 30 , 31 , 32 ]. Our findings clearly highlight the potential of CTN to cause post-implantation development injury.…”

“…Accumulating experimental evidence has highlighted a critical role of LQ as a scavenger of intracellular ROS that inhibits or regulates ROS-mediated signaling pathways to protect various cell types against injury or damage, including human umbilical vein endothelial cells (HUVECs), neurons, hippocampal neurons, macrophages, hepatocytes and osteoblasts [ 19 , 21 , 30 , 31 , 32 ]. The intracellular ROS level is a key regulator of apoptotic processes in several cell models [ 35 , 36 ].…”

Prevention of ochratoxin A‐induced oxidative stress‐mediated apoptotic processes and impairment of embryonic development in mouse blastocysts by liquiritigenin

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Activation of AMPK by Buddleja officinalis Maxim. Flower Extract Contributes to Protecting Hepatocytes from Oxidative Stress

“…Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by using analysis kits (Pointe Scientific Inc., Canton, MI, USA) and an automated blood chemistry analyzer (Photometer 5010; Robert Riele GmbH & Co. KG, Berlin, Germany) according to manufacturer's instructions [20]. …”