Window of opportunity: Estrogen as a treatment for ischemic stroke

Abstract

The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials.

High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke

“…There has been an increasing interest in using estrogens after the onset of ischemic stroke, alone or in combination with other strategies, to promote neuroprotection and functional recovery (reviews by Liu & Yang 2013, Schreihofer & Ma 2013). In the current study, E2 treatment was able to remarkably decrease lesion volume and accelerate recovery of forelimb function when administered at the time of reperfusion in an experimental stroke model in rats.…”

DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats

“…Approximately, one in six people will have a stroke in their lifetime [1], and the risk of having a stroke more than doubles each decade after the age of 55 [2]. Despite current attention to stroke-risk factors and preventive treatment, the number of stroke cases has been increasing in recent decades, probably due to the aging population [3].…”

Female Reproductive Factors and Major Eye Diseases in Asian Women –The Singapore Malay Eye Study

“…[26][27][28] In addition, 17-beta-estradiol and progesterone play important roles in the regulation of synaptic plasticity and neurodegeneration. [29][30][31] Developmentally, the optic nerve and retinal ganglion cells are known as an extension of the central nervous system and neurodegenerative diseases affecting the brain and spinal cord have often shown manifestations within the eye. 32 Hence, the protective effects of estrogen and progesterone in the central nervous system can be extrapolated to include the optic nerve and retina in the eye.…”