Electroacupuncture reactivates estrogen receptors to restore the neuroprotective effect of estrogen against cerebral ischemic stroke in long‐term ovariectomized rats

Abstract

Background: Stroke is a sexually dimorphic disease and a leading cause of death and disability. Estrogen replacement therapy (ERT) confers beneficial neuroprotective effects if administered within a widely accepted time window called the "critical period." However, very few studies have explored the idea of modulating the critical period to enable long-term post-menopausal women to regain more benefits from estrogen therapy. Here, motivated by previous findings that electroacupuncture could both alter estrogen metabolism and induce significant tolerance against stroke, it was explored whether EA could restore estrogen's neuroprotection against cerebral ischemia in long-term ovariectomized (OVX) rats. Methods:We implemented 1 week(w)-EA pretreatment on OVX-10w or OVX-20w rats, and tested the expression of estrogen receptors, and detected the ERT's neuroprotection against stroke induced by middle cerebral artery occlusion (MCAO). Results:We found that the expression levels of phospho-ERα-S118 and estrogen receptor β (ERβ) in the striatum of OVX-10w rats were significantly decreased and ERT's neuroprotection was abolished in the OVX-10w rats. However, EA-1w pretreatment could significantly recover the expression levels of phospho-ERα-S118 and ERβ, and also restored the neuroprotective effects of ERT in OVX-10w rats. However, EA-1w pretreatment could not restore the expression of estrogen receptors and ERT's neuroprotection in OVX-20w rats. Conclusion:Taken together, our study indicates that EA may be an easy intervention that can restore the efficacy of estrogen therapy during the "critical period," which has the potential to improve the stroke outcomes of an enormous number of longterm post-menopausal women. However, the time-sensitive influences for how EA and estrogen metabolism interact with each other should be considered.

Supraphysiologic doses of 17β-Estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism

“…This observation indicated that the effective dose range of E2 for neuroprotection was narrow, probably due to the different receptors and signaling pathways activated by different concentrations of E2. Previous reports have shown that E2 shows neuroprotective effects primarily through ERβ and CPER [52][53][54]. In the microglia, the activation of NF-κB plays a critical role in the production of proin ammatory cytokines, leading to the neurotoxic effect [55].…”

Sex differences in outcomes after endovascular treatment of patients with vertebrobasilar artery occlusion

“…26 It is reported in previous data that estrogen has a neuroprotective effect on ischemic stroke. 27 However, the level of menopause and estrogen decline rapidly in elder women It has been demonstrated from epidemiological studies that the majority of strokes in postmenopausal women are more severe, lead to poorer psychological outcomes, and result in higher rates of disability. 28 A recent study of the effect of sex on the outcome of mechanical thrombectomy in basilar artery occlusion (BAO) showed that women achieved comparable functional outcomes compared with men after undergoing mechanical thrombectomy.…”

“…26 It is reported in previous data that estrogen has a neuroprotective effect on ischemic stroke. 27 However, the level of menopause and estrogen decline rapidly in elder women It has been demonstrated from epidemiological studies that the majority of strokes in post-menopausal women are more severe, lead to poorer psychological outcomes, and result in higher rates of disability. 28…”

Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex

“…To date, three types of ERs have been identified: ERα, ERβ, and G-protein coupled receptors ( 37 – 39 ). Reportedly, estrogen mediates its effects via two signaling pathways ( 40 ). The first is the genomic pathway, which involves ERα and ERβ.…”