Article

Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke.

Departments of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, 76107, TX, USA.
Brain research (Impact Factor: 2.83). 01/2013; DOI: 10.1016/j.brainres.2013.01.023
Source: PubMed

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.

0 Followers
 · 
258 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for. The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats. We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions.
    BMC Neuroscience 02/2014; 15(1):22. DOI:10.1186/1471-2202-15-22 · 2.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background A vast scientific literature has dealt with gender-specific risk for brain disorder. That field is evolving toward a consensus to the effect that the estrogen hormone family is outstandingly and uniquely neuroprotective. However, the epidemiology relevant to this general outlook remains piecemeal. Method The present investigation strategically formats the relevant epidemiological findings around the world in order to quantitatively meta-analyze gender ratio of risk for a variety of relevant severe central nervous system (CNS) diseases at all three gonadal stages of the life cycle, pre pubertal, post adolescent/pre menopausal, and post menopausal. Results The data quantitatively establish that 1) no single epidemiological study should be cited as evidence of gender-specific neuroprotection against the most common severe CNS diseases because the gender-specific risk ratios are contradictory from one study to the other; 2) risk for severe CNS disease is indeed significantly gender-specific, but either gender can be protected: it depends on the disease, not at all on the age bracket. Conclusion Our assay of gender-specific risk for severe brain disease around the world has not been able to support the idea according to which any one gender-prevalent gonadal steroid hormone dominates as a neuroprotective agent at natural concentrations.
    International Journal of Developmental Neuroscience 11/2014; DOI:10.1016/j.ijdevneu.2014.07.009 · 2.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischemic lesion rapidly die and other neuronal populations in the ischemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischemia and are dissecting the functional importance of this regenerative mechanism following brain injury.
    The International Journal of Biochemistry & Cell Biology 08/2014; DOI:10.1016/j.biocel.2014.08.003 · 4.24 Impact Factor

Full-text

Download
167 Downloads
Available from
May 19, 2014