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. This article is part of a Special Issue entitled Hormone Therapy.

Figure 1. Schematic presentation of the potential mechanisms underlying the combined rtPA/estrogen treatment for ischemic stroke

Upper panel: Combined estrogen treatment expands therapeutic window of rtPA for the treatment of ischemic stroke. Lower panel: The neurovascular unit neurovascular unit showing functional interactions between the vascular and cellular components the integrative response of brain to ischemia. Ultimately, strategies that view the neurovascular unit as an integrative unit whose compromise contributes to brain damage after ischemic stroke could guide the future of the treatment for ischemic stroke. As indicated, estrogens have profound effects on both vascular and cellular components of neurovascular unit under ischemia insult. Estrogen might not only provide protection but also antagonize many detrimental action of rtPA.