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Abstract
Postmenopausal women have a higher incidence of stroke compared to the age-matched males, and the estrogen was thought to be the main cause of such difference. However, estrogen replacement therapy for the prevention of postmenopausal stroke shows controversial results and is widely disputed because of its serious side effects after chronic administration. Genistein (Gen), a natural phytestrogen with fewer side effects, has a protective effect against cerebral ischemia damage. However, whether Gen could effectively prevent postmenopausal stroke has not been elucidated. In the current study, reproductively senescent mice were treated with Gen (10 mg/kg) for 2 weeks before having transient cerebral ischemia insults. Neurological scores, infarct volumes, and cell apoptosis were evaluated 24 h after reperfusion. The levels of inflammatory factors and nod-like receptor protein 3 (NLRP3) inflammasome-related proteins were also examined. The results showed that Gen treatment reduced infarct volumes, improved neurological scores, attenuated apoptosis, and decreased inflammatory factor release. The expression of NLRP3 inflammasome-related proteins in microglia was downregulated by Gen. However, the overexpression of NLRP3 in microglia abrogated the Gen-induced inhibition of inflammatory factor release and reversed the neuroprotective effect of Gen. Taken together, the results suggest that Gen treatment could attenuate the acute injury induced by cerebral ischemia in reproductively senescent mice via the inhibition of the NLRP3 inflammasome in microglia, indicating that Gen could be a candidate drug for the treatment of stroke in postmenopausal women.
Highlights
Compared with the age-matched men, the incidence of stroke in women is lower in premenopausal period but significantly increases after menopause (Haast et al, 2012)
The current study demonstrated that the administration of Gen in the reproductively senescent mice could reduce the infarct volume, improve the neurological scores, decrease the neuronal apoptosis, and reduce the release of inflammatory factor release
We found greater than 80% of nod-like receptor protein 3 (NLRP3) was expressed in the microglia within 24 h after middle cerebral artery occlusion (MCAO) in the reproductively senescent mice, we subsequently chose the microglia as the target of this study
Summary
Compared with the age-matched men, the incidence of stroke in women is lower in premenopausal period but significantly increases after menopause (Haast et al, 2012). Estrogen is the main cause of the sex differences in stroke incidence. Many animal studies have confirmed that estrogen has a strong neuroprotective function. The hormone therapy could decrease the risk of stroke in postmenopausal women (Henderson and Lobo, 2012), and the treatment with conjugated equine estrogens for 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a Genistein Prevents Stroke via NLRP3 cumulative follow-up of 18 years (Manson et al, 2017), hormone therapy increases the risk of other undesired consequences, such as invasive breast cancer, intracerebral hemorrhage, and venous thromboembolism (Gartlehner et al, 2017). Natural food-derived compounds with structures and functions similar to estrogen could be alternatives to postmenopausal hormone therapy with fewer side effects. We hypothesized that Gen supplementation could potentially be effective in protecting against stroke in the reproductively senescent animals
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