Proceedings of The Physiological Society
University College Dublin (2009) Proc Physiol Soc 15, PC142
The effect of synthetic analogues of the phyto-oestrogen 8-prenylnaringenin on tail skin temperature in a rat hot flush model
L. Breen1, D. Sugden1, A. Heyerick2, K. O'Byrne1, S. Milligan1
1. Division of Reproduction and Endocrinology, King's College London, London, United Kingdom. 2. Laboratory of Pharmacognosy and Phytochemistry, Ghent University, Ghent, Belgium.
Hot flushes are a distressing symptom of the menopausal syndrome affecting over 75% of women, many of whom seek medical treatment because of the severity of the symptoms. There has been growing interest in the use of phyto-oestrogens as alternative therapies for hot flushes due to recent reports highlighting adverse effects of oestrogen therapy. A potent oestrogenic compound in hops (Humulus lupulus) has been identified as 8-prenylnaringenin (8-PN) and hop extracts containing 8-PN have been used for treating menopausal symptoms, including hot flushes. Synthetic analogues of 8-PN, 8-neopentylnaringenin and 8-n-heptylnaringenin, have been demonstrated to be selective oestrogen receptor modulators in vitro. We have investigated the in vivo oestrogenic activity of these compounds using a rat model of the hot flush phenomenon in which the tail skin temperature (TST) is increased after oestrogen deficiency induced by ovariectomy. Female Wistar rats were ovariectomized and implanted with chronic telemetry devices (TA10TA-F40 W/TP; Data Sciences International) under general anaesthesia induced by ketamine hydrochloride (100mg/kg) co-administered with medetomidine (0.5mg/kg) ip. On completetion of surgery, anaesthesia was reversed by atipamezole (1mg/kg) sc. After a two week recovery period TST was monitored for 7 sec every 5 min throughout the experimental period. Following a three day monitoring period to establish baseline temperatures, 17β-oestradiol (E2), vehicle, 8-neopentylnaringenin or 8-n-heptylnaringenin were administered subcutaneously daily for five days. Administration of E2 (4µg/kg) significantly reduced the elevated TST on the fifth and final day of injection by 1.89 ± 0.14oC from the baseline TST (paired Students t-test, P<0.0001; n=8). In addition, 8-neopentylnaringenin (20mg/kg), a strong oestrogen receptor (ER)α agonist and weak ERβ antagonist, significantly reduced TST by 1.12 ± 0.12oC (paired Students t-test, P<0.0002; n=6). In contrast, 8-n-heptylnaringenin (20mg/kg), a weak ERα agonist and strong ERβ antagonist, did not significantly reduce the elevated TST when administered alone and failed to block the E2 induced decrease in TST when co-administered with E2. These results indicate that analogues of 8PN are effective in the rat model of hot flushes and deserve further investigation.
Where applicable, experiments conform with Society ethical requirements