Neuroprotective effects of liquiritigenin isolated from licorice roots on glutamate-induced apoptosis in hippocampal neuronal cells

Yang, Eun‐Ju; Park, Gyu Hwan; Song, Kyung‐Sik

doi:10.1016/j.neuro.2013.08.012

Cited by 59 publications

(41 citation statements)

References 40 publications

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“…25,26) Moreover, others have shown LQ is a plant-derived selective estrogen receptor-β agonist with neuroprotective effects on glutamateinduced apoptosis in hippocampal neuronal cells. 36,37) In the present study, LQ protected hepatocytes from cytotoxicity induced by tacrine, as evidenced by the inhibition of cellular H 2 O 2 production and mitochondrial dysfunction and by the restoration of the intracellular concentration of GSH. Pretreatment with LQ also inhibited tacrine-induced liver damage, as assessed by inhibitions of the up-regulations of ALT and AST and by hepatocyte degeneration and inflammation in liver tissue.…”

Section: Discussionsupporting

confidence: 56%

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

Park

Han

et al. 2015

Biological & Pharmaceutical Bulletin

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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 ...

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Section: Discussionsupporting

confidence: 56%

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

Park

Han

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Metabolic analysis of LQ after absorption in rats revealed breakdown into six metabolites that localize to liver microsomes, including 7,3′,4′‐trihydroxyflavone, a hydroxyl quinine metabolite, and two A‐ring dihydroxy metabolites, 7,4′‐dihydroxyflavone and 7‐hydroxychromone . Protective effects of LQ have been reported against glutamate‐induced apoptosis in hippocampal neuronal cells, heavy metal‐triggered toxicity in cultured hepatocytes, liver toxicity in rats, and methylglyoxal‐exposed cytotoxicity in osteoblastic MC3T3‐E1 cells . In addition, LQ can effectively protect or abolish oxidative stress‐induced harmful impacts via anti‐oxidative activity that is predominantly based on its chemical structure.…”

Section: Introductionmentioning

confidence: 99%

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

Huang

Wang

Chan

2019

Environmental Toxicology

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“…Liquiritigenin (Liq) is a herb-derived, highly selective ERβ agonist (16). It activates multiple regulatory elements and downstream target genes of ERβ with high specificity, and exhibits various anti-inflammatory (17,18) and antitumor effects (19,20). It has been shown that Liq inhibits the production of inducible nitric oxide synthase and the release of proinflammatory cytokines in macrophages (17).…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

Liu

Wang

Chen

et al. 2014

Molecular Medicine Reports

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Glioma is the most common primary brain tumor among adults. Temozolomide (TMZ) is widely used as the first‑line postsurgical drug for malignant glioma. However, the therapeutic efficacy of TMZ remains ineffective as inherited or acquired drug resistance is frequently observed. Estrogen receptor β (ERβ) has emerged as a tumor suppressor and a key regulator of signal transduction in glioma cells. However, little is known about the role of ERβ in regulating the chemotherapeutic response to TMZ. In the current study, the TMZ‑resistant U138 glioma cells were treated with the novel ERβ agonist liquiritigenin (Liq). It was observed that Liq significantly enhanced ERβ expression and sensitized glioma cells to TMZ‑induced proliferation inhibition. As a potential mechanism, it was noted that Liq treatment significantly inhibited the activity of the PI3K/AKT/mTOR pathway, which played a protective role against the TMZ‑induced cytotoxicity. In addition, it was demonstrated that ERβ knockdown or activation of the phosphatidylinositol‑4,5‑bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway by insulin‑like growth factor 1 both eradicated the function of Liq. These results suggest that Liq treatment enhances glioma cell susceptibility to TMZ by inhibiting the PI3K/AKT/mTOR pathway. As hyperactivation of the PI3K/AKT/mTOR pathway is frequently observed in gliomas, the combined use of ERβ agonists may become a feasible therapy option to overcome chemoresistance to TMZ.

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Neuroprotective effects of liquiritigenin isolated from licorice roots on glutamate-induced apoptosis in hippocampal neuronal cells

Cited by 59 publications

References 40 publications

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

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

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

Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

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