A large body of research has shown that estrogens can modulate learning and memory. Importantly, the effects of estrogens on cognition vary based on several factors including dose, the type of estrogen used, the age of the animal, the length of exposure, the route of exposure, as well as the demands of the cognitive task. Botanical estrogens are non-steroidal plant compounds that can mimic estrogens in the body by binding to estrogen receptors and affecting transcriptional changes. Many botanical estrogens are widely available over the counter in dietary supplements, despite a dearth of research about their effects. This work investigated the efficacy of components of licorice root, one of the most common sources of botanical estrogens in dietary supplements, to alter performance on three different cognitive tasks: a prefrontal cortex-sensitive delayed spatial alternation (DSA) task, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. ISL is a pure compound found in licorice root with known estrogenic activity. LRE and LRP are both complex mixtures containing ISL as well as other components. Working memory was assessed in the DSA study. Middle-aged female rats were ovariectomized (OVX) and exposed to ISL (0, 6, 12, or 24 mg) once per day through pellets. Exposure to ISL did not affect DSA performance at any of the three doses tested. Estrogens have been shown to impair performance on the DSA task in previous studies. Spatial object location memory was assessed in three separate studies using the MCOL task. Object recognition memory was assessed using the DOR task. In the MCOL and DOR studies, young-adult female rats were OVX and exposed to ISL, LRE or LRP continuously through the diet at concentrations of 0.075%, 0.5% and 5% respectively for three weeks. Estradiol groups were also included in each MCOL and DOR study. The effects of these compounds in animals fed high fat (44.8% kcal from fat) or low fat (17.2% kcal from fat) diets were also assessed. The high fat diet is more similar to the Western diet and was included to more closely model the human population consuming botanical estrogen supplements.In the MCOL studies, ISL and LRE were found to mimic the effects of estradiol and improve performance on the MCOL task in young-adult OVX rats. LRP did not affect performance on the MCOL task. There was no effect of dietary fat and no interaction between dietary fat and exposure to the botanicals or estradiol in the MCOL studies, thus diet was not included as a factor in the DOR study. In the DOR study, estradiol impaired performance on the task, replicating previous findings. Exposure to ISL, LRE or LRP did not affect performance on the DOR task. Because of the significant cognitive effects of ISL and LRE seen on the hippocampus-sensitive MCOL task, gene and protein expression of several estrogen-sensitive targets known to be involved in cognition in the hippocampus were also assessed. RT-qPCR was used to measure gene expression of Bdnf, Ntkr2, Dlg4, Gria1, Gria2, Grin1, Grin2B, Esr1 and Esr2. There were no significant changes in the expression of any of the chosen genes with exposure to the botanical compounds or estradiol. However, there was a trend for reduced expression of three genes. Western blotting was used to measure protein expression of these genes: PSD-95, GluR1, and GluR2. ISL, LRE, LRP and estradiol failed to modulate levels of those proteins. These findings suggest that ISL and LRE may, like other estrogens, enhance performance on some hippocampus-sensitive tasks in young-adult OVX rats, while potentially avoiding some of the deleterious cognitive effects of some other estrogens tested to date.
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The effects of licorice root components on cognition
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