Liquiritigenin Attenuates Alzheimer’s-Like Neuropathology in an Amyloid Protein Precursor Transgenic Mouse Model and the Underlying Mechanisms

Estrogen plays a key regulatory role in a number of biological processes and, in addition to its classic function as a sex hormone, it has been linked to neurodegenerative diseases, including Alzheimer's disease (AD) (Wickelgren, 1997; Brann et al., 2007; Zhang et al., 2007). However, long-term compliance with estrogen therapy is often estimated to be no more than 15%–40%, due to its undesirable side-effects, such as an increased risk of developing breast and uterine cancer (Warren, 2004). Therefore, the body of recent research has focused on finding neuro-selective estrogen receptor agonists (Zhao et al., 2005) that mimic the beneficial effects of estrogen in the brain but which also exert negligible adverse effects on non-neural estrogen-responsive tissues. For instance, propylpyrazole triol and diarylpropionitrile – each of which exhibits relative specificity for the estrogen receptors ER┙ and ER┚ respectively – have been proven to differentially regulate AD-like changes in female AD model mice (Carroll and Pike, 2008). Additionally, some phytoestrogens with fewer side-effects and potential neuroprotective effects have been developed for use in alternative treatment strategies (Zhao et al., 2002; Bang et al., 2004). Liquiritigenin (7, 4’-dihydroxyflavanone) is a flavonoid extracted from the radix of Glycyrrhiza, an herbal that is frequently used to treat injury or swelling, or for detoxification in traditional Oriental medicine. Liquiritigenin is also one of the major active compounds of MF101 (Kupfer et al., 2008), an herbal extract currently used in clinical trials for the treatment of hot flushes and night-sweats in post-menopausal women. Our interest in liquiritigenin is based upon the following observations. First, liquiritigenin is shown to be a selective agonist of estrogen receptor-┚ (ER┚) (Mersereau et al., 2008). ER┚ is expressed in the brain centre related to learning and memory, but it is unlikely to be related to sex (Shughrue et al., 1997; Gustafsson et al., 2003). Second, studies have already proven that liquiritigenin exerts cytoprotective effects in vitro and in vivo (Kim et al., 2004; Kim et al.,