The effects of the botanical estrogen, isoliquiritigenin on delayed spatial alternation

Abstract

Age-related declines in cognitive function can impair working memory, reduce speed of processing, and alter attentional resources. In particular, menopausal women may show an acceleration in the rate of cognitive decline as well as an increased vulnerability to brain diseases as estrogens may play a neuroprotective and neurotrophic role in the brain. To treat menopausal symptoms, many women turn to botanical estrogens that are promoted as a safe and natural alternative to traditional hormone replacement therapy. However, the majority of these compounds have not been systematically evaluated for efficacy and safety. The current study investigated the efficacy of the commercially available botanical estrogenic compound isoliquiritigenin (ISL) to alter performance on an operant working memory task, delayed spatial alternation (DSA). ISL is a compound found in licorice root that has been shown to have a wide range of effects on different biological systems, including estrogenic properties. This botanical is currently being used in over the counter dietary supplements. Middle-aged (12-month old) Long-Evans female rats were ovariectomized and orally dosed with either 0 mg, 6 mg, 12 mg or 24 mg of ISL 60 min before testing on the DSA task. The DSA task required the rat to alternate its responses between two retractable levers in order to earn food rewards. Random delays of 0, 3, 6, 9 or 18 s were imposed between opportunities to press. ISL treatment failed to alter DSA performance. Previous work from our research group has found that estrogenic compounds, including 17β-estradiol and the botanical estrogen genistein impair performance on the DSA task. The goal of our botanical estrogens research is to find compounds that offer some of the beneficial effects of estrogen supplementation, without the harmful effects. This work suggests that ISL may not carry the cognitive risks associated with most other estrogenic compounds tested to date.

Keywords: Aging; Isoliquiritigenin; Phytoestrogens; Prefrontal; Working memory.

Figure 1

Serum ISL and LIQ levels from a pilot study prior to the current study in female rats (n=6) provided 1 pellet containing 10 mg ISL (dose of ~32 mg/kg body weight. A) Total serum levels of ISL and LIQ across a 24 hour period. B.) Aglycone serum levels of ISL and LIQ across a 24 hour period.

Figure 2

There was no main effect of exposure on the days to criterion in the autoshaping phase of training (n=16).

Figure 3

A) There was no main effect of exposure on the total number of errors during the cued alternation phase of training (n=16). B) There was no main effect of exposure on the days to reach criterion on the cued alternation phase of training (n=16).

Figure 4

A) There was no main effect of exposure on the proportion correct during the non-cued alternation phase of training (n=16). B) All groups increased in their proportion correct across sessions of NCA, but did not differ significantly from each other (n=16).

Figure 5

A) (Left panel) There was no main effect of exposure on the proportion correct in the DSA task. There was also no interaction between exposure and block, indicating that all groups performed similarly within testing blocks (n=16). B) (Right panel) There was no interaction between exposure and delay in the DSA task, indicating that all groups performed similarly within each delay (n=16)

Figure 6

A) (Left panel) There was no main effect of exposure on the size of the uterine horn (n=16). B) (Right panel) There was no main effect of exposure on the liver weight to body weight ratio (n=16).