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      Pathways to ischemic neuronal cell death: are sex differences relevant?

      review-article
      1 , 1 , 2 ,
      Journal of Translational Medicine
      BioMed Central

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          Abstract

          We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. Now, a new concept is emerging: the mechanisms and outcome of cerebral ischemic injury are influenced strongly by biological sex as well as the availability of sex steroids to the brain. The principal mammalian estrogen (17 β estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However, it is becoming increasingly clear that although hormones are a major contributor to sex-specific outcomes, they do not fully account for sex-specific responses to cerebral ischemia. The purpose of this review is to highlight recent studies in cell culture and animal models that suggest that genetic sex determines experimental stroke outcome and that divergent cell death pathways are activated after an ischemic insult. These sex differences need to be identified if we are to develop efficacious neuroprotective agents for use in stroke patients.

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          Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications.

          Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neurotrophic and neuroprotective actions of estrogen in the brain, with particular emphasis on estrogen actions in the hippocampus, cerebral cortex and striatum. Sex differences in the risk, onset and severity of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease and stroke are well known, and the potential role of estrogen as a neuroprotective factor is discussed in this context. The review assimilates a complex literature that spans research in humans, non-human primates and rodent animal models and attempts to contrast and compare the findings across species where possible. Current controversies regarding the Women's Health Initiative (WHI) study, its ramifications, concerns and the new studies needed to address these concerns are also addressed. Signaling mechanisms underlying estrogen-induced neuroprotection and synaptic plasticity are reviewed, including the important concepts of genomic versus nongenomic mechanisms, types of estrogen receptor involved and their subcellular targeting, and implicated downstream signaling pathways and mediators. Finally, a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field.
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            Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration.

            Comparing stroke rates in different parts of the world may increase our understanding of both etiology and prevention. However, comparisons are meaningful only if studies use standard definitions and methods, with comparably presented data. We compared the incidence of stroke and its pathological types (cerebral infarction, primary intracerebral hemorrhage, and subarachnoid hemorrhage) in recent studies from around the world. Studies with a midyear of 1984 or later, fulfilling standard criteria for a comparable, community-based study, provided original data for comparative analyses. By mid-1995, data were available from 11 studies in Europe, Russia, Australasia, and the United States, comprising approximately 3.5 million person-years and 5575 incident strokes. Age- and sex-standardized annual incidence rates for subjects aged 45 to 84 years were similar (between approximately 300/100,000) and 500/100,000) in most places but were significantly lower in Dijon, France (238/100,000), and higher in Novosibirsk, Russia (627/100,000). In subjects aged 75 to 84 years, however, Novosibirsk no longer ranked higher than the other studies. The distribution of pathological types, when these were reliably distinguished, did not differ significantly between studies. The similarities in stroke incidence and pathological types are perhaps not surprising given that all the populations were westernized and mainly white. The higher rates in Novosibirsk, disappearing in the elderly, and the lower rates in Dijon have several potential explanations. These include methodological artifact and different patterns of population risk factors. Further work is needed to explore these possibilities and to extend our knowledge of stroke incidence to other parts of the world, especially developing countries.
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              Two Distinct Pathways Leading to Nuclear Apoptosis

              Apaf-1−/− or caspase-3−/− cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1−/− or caspase-3−/− cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1−/− or caspase-3−/− cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation.
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                Author and article information

                Journal
                J Transl Med
                Journal of Translational Medicine
                BioMed Central
                1479-5876
                2008
                23 June 2008
                : 6
                : 33
                Affiliations
                [1 ]Departments of Neurology and Neuroscience, The University of Connecticut Health Center, Farmington, CT, USA
                [2 ]The Stroke Center, Hartford Hospital, Hartford, CT, USA
                Article
                1479-5876-6-33
                10.1186/1479-5876-6-33
                2459157
                18573200
                c18fe862-ac76-4c99-9e67-5da667ec4294
                Copyright © 2008 Lang and McCullough; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 May 2008
                : 23 June 2008
                Categories
                Review

                Medicine
                Medicine

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