Abstract: Objective: To investigate the effects of osthole, a natural coumarin first derived from the Cnidium plant, on learning and memory, physiological and pathological changes, and expression of estrogen receptor (ER) α and β in the brain of ovariectomized (OVX) rats of Alzheimer's disease (AD) models. Methods: Female rats were randomly divided into six groups: 1) sham operation, and OVX plus: 2) saline, 3) Estradiol (0.1 mg/kg; positive control), 4) osthole at 12.5 mg/kg, 5) osthole at 25 mg/kg, and  5) osthole at 50 mg/kg; intragastric administration for 30 days. The Morris water-maze test was used to evaluate the learning and memory ability of rats, ELISA to measure the levels of estradiol in the serum, Western blotting to detect the expression of ERα and ERβ in the hippocampus, and HE staining to determine the histopathological changes in the brain. Results: 1. Effects on learning and memory: compared to the OVX alone, osthole at 25 or 50 mg/kg significantly increased the number of entries and the duration in the target quadrant in the water-maze probe trial test (P<0.05). 2. Effects on the estrogen pathway in the brain: the level of estradiol in the serum and expression of ERβ in the hippocampus in the OVX alone were significantly lower, while the expression of ERα was higher, relative to the sham operation control (P<0.01); osthole at 25 mg/kg reversed the OVX-induced changes in expression of ERα and ERβ (P<0.01). 3. Effects on histopathological change in the brain: in comparison with the sham operation group, the OVX rats treated with saline displayed increases in the number of apoptotic cells in the hippocampus, which was reversed by osthole at 25 or 50 mg/kg  (P<0.05), but not the lower dose of 12.5 mg/kg. Conclusion: Osthole produced enhancement of learning and memory in the ovariectomized dementia model, which was mediated, at least in part, by regulating neuronal apoptosis and the estrogen pathway. Therefore, osthole is potent in delaying the development of female neurodegenerative diseases, which provides a potential, new approach to treatment of female AD.

Key words: Osthole, Estradiol, Alzheimer&rsquo, s disease, Ovariectomized, learning and memory