Abstract
Background: Impairment of memory and cognition is one of the major symptoms in women with postmenopausal disorders due to estrogen deficiency, which accounts for the much higher prevalence of Alzheimer’s disease in females. Biochanin A (BCA), a natural phytoestrogen, has been reported to protect neurons against ischemic brain injury. However, the neuroprotective effects of BCA in the postmenopausal-like model of ovariectomized (OVX) rats remain to be investigated. Methods: All the rats except for the sham group underwent the resection of bilateral ovaries. Seven days after the OVX surgery, rats were randomly divided into six groups: sham, OVX, OVX + BCA (5 mg/kg), OVX + BCA (20 mg/kg), OVX + BCA (60 mg/kg), and OVX + estradiol (E2; 0.35 mg/kg), which were administrated daily by gavage for 12 weeks. Learning and memory were examined using the Morris water-maze test before the end of the experiment. Morphological changes of the rat hippocampus were observed by HE staining and electron microscopy. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the hippocampus were measured. The effect of BCA on cell viability was measured in the presence of hydrogen peroxide (H2O2) using CCK8. Flow cytometry was used to measure neuronal apoptosis and reactive oxygen species (ROS) induced by H2O2. Expression of Bcl-2, Bax, and Caspase-3 was determined by Western blotting using hippocampal tissues and primary cultures of hippocampal neurons. Results: Chronic treatment with BCA mimicked the ability of E2 to reverse the deficit of learning and memory in the Morris water-maze test in OVX rats. BCA normalized OVX-induced morphological changes as revealed by HE staining and electron microscopy. In addition, BCA significantly decreased the levels of MDA, the biomarker of oxidative damage, and increased the activity of the intracellular antioxidant enzymes SOD and GSH-Px in OVX rats. Further, in primary cultures of hippocampal neurons, BCA reversed H2O2-induced decreases in cell viability and accumulation of ROS. Finally, BCA reversed OVX- or H2O2-induced increases in Bax and Caspase-3 and decreases in Bcl-2 in the hippocampus and primary cultures of hippocampal neurons. Conclusion: These results suggest that BCA improves memory through its neuroprotective properties in the brain under the circumstance of estrogen deficiency and can be used for treatment of memory loss in postmenopausal women.
Highlights
Gender is a strong contributor to the vulnerability to Alzheimer’s disease (AD), the most common neurodegenerative disease and the primary cause for dementia
Compared to the sham controls, OVX rats showed significant decreases estradiol in serum (F(5,54) 4.89, p < 0.05; Figure 1B), suggesting a successful model of OVX. This was blocked by estradiol (p < 0.01); Biochanin A (BCA) mimicked the ability of estradiol to increase estrogen contents in OVX rats (p < 0.05; Figure 1B)
The OVX rats had longer escape latency (F (5,54) 3.95, p < 0.05), indicating spatial learning impairment induced by OVX (Figure 2A,B); this was attenuated by treatment with BCA and estradiol (p < 0.05)
Summary
Gender is a strong contributor to the vulnerability to Alzheimer’s disease (AD), the most common neurodegenerative disease and the primary cause for dementia. Two-thirds of AD patients are females, in particular postmenopausal women, contributing to over 60% of all those affected (Brookmeyer et al, 2011). This suggests that deficiency of estrogens is a critical risk factor of AD in women under the postmenopausal condition. Impairment of memory and cognition is one of the major symptoms in women with postmenopausal disorders due to estrogen deficiency, which accounts for the much higher prevalence of Alzheimer’s disease in females. The neuroprotective effects of BCA in the postmenopausal-like model of ovariectomized (OVX) rats remain to be investigated
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