{"id":611,"date":"2017-02-24T04:45:43","date_gmt":"2017-02-24T09:45:43","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=611"},"modified":"2017-02-24T04:45:43","modified_gmt":"2017-02-24T09:45:43","slug":"estrogen-as-a-neuroprotective-agent","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/estrogen-as-a-neuroprotective-agent\/","title":{"rendered":"Estrogen As a Neuroprotective Agent"},"content":{"rendered":"<p>Since Ed Hall and colleagues first discovered that female gerbils were relatively\u00a0protected from global cerebral ischemia, compared with their male counterparts, in the\u00a0early 1990s (Hall et al., 1991), gender differences have been a major focus of\u00a0neurological research. Intriguingly, according to Scott et al. (2012), \u201cgender differences\u00a0exist in most disorders affecting the central nervous system (CNS), particularly the\u00a0neurodegenerative conditions, with women typically having a later onset and greater\u00a0severity of disease (Tang et al., 1996, Brann et al., 2007). Women\u2019s relative protection,\u00a0later onset, and greater severity of neurodegenerative disorders can be explained, in part,\u00a0by serum levels of the neuroprotective ovarian hormone, 17p~estradiol (estradiol or E2).\u00a0From birth to menopause, women\u2019s ovaries produce high circulating levels o f estradiol,\u00a0which correlates with a low incidence o f neurodegenerative disease. However, once the\u00a0menopausal transition occurs, the ovaries cease to [produce] E2, and women\u2019s risk for\u00a0neurodegenerative diseases, including ischemic stroke and <a href=\"http:\/\/www.bocsci.com\/tag\/alzheimer-s-disease-389.html\">Alzheimer\u2019s disease<\/a>, increases\u00a0(Brann et al., 2007). One could dismissively attribute this correlation to senescence.\u00a0However, women who enter menopause prematurely via bilateral oophorectomy (surgical\u00a0removal of both ovaries) have a doubled lifetime risk for developing dementia, as well as\u00a0a significantly increased risk of cognitive decline, <a href=\"http:\/\/www.bocsci.com\/anti-parkinsonism-rlist-1318.html\">Parkinson\u2019s disease<\/a>, and mortality\u00a0from neurological disorders (Rocca et al., 2007, Shuster et al., 2010, Rocca et al., 2011).\u00a0Furthermore, meta-analyses of observational studies demonstrated that postmenopausal\u00a0women who used oral estrogens had a 29-44% reduced risk o f Alzheimer\u2019s disease\u00a0(Yaffe et al., 1998, Hogervorst et al., 2000, Brann et al., 2007).<\/p>\n<p>In further support of the correlation between high serum levels of estradiol and\u00a0women\u2019s relatively low risk of neurodegenerative disease, studies in rodents have\u00a0overwhelmingly demonstrated that E2 is a neuroprotective agent. Female rodents were\u00a0less susceptible to ischemic stress via experimental stroke procedures, such as middle\u00a0cerebral artery occlusion (MCAO) and global cerebral ischemia (GCI), than their male\u00a0counterparts, and ovariectomy prior to stroke induction abolished this gender difference\u00a0(Brann et al., 2007). Serum E2 levels in intact rodents were also found to be inversely\u00a0correlated with stroke infarct size (Liao et al., 2001), and pre-treatment with ICI 182,780,\u00a0a competitive antagonist of both estrogen receptor isoforms alpha (ERa) and beta (ER(3),\u00a0prior to stroke induction actually enhanced the size of the infarct (Sawada et al., 2000).\u00a0Additionally, pre-treatment with aromatase inhibitors, which prevent the conversion of\u00a0androgens to estrogens, exacerbated ischemic injury in rodent brains, and aromatase\u00a0knockout (KO) mice, which are physically unable to convert testosterone into estradiol,\u00a0also had larger infarct volumes after MCAO (McCullough et al., 2003). Conversely, pretreatment with exogenous E2 decreased mortality and infarct size following MCAO and\u00a0GCI in rodents (Simpkins et al., 1997, Dubai et al., 1998, Shi et al., 1998, Zhang et al.,\u00a01998, Rusa et al., 1999, Jover et al., 2002, Shughrue and Merchenthaler, 2003,\u00a0McCullough et al., 2005, Brann et al., 2007, Zhang et al., 2008, Lebesgue et al., 2009,\u00a0Zhang et al., 2009a, Yang et al., 2010, Zhang et al., 2011). A systematic review o f 161\u00a0publications on estradiol and stroke performed by Gibson et al. further confirmed a dosedependent reduction of stroke lesion volume by E2 in models of transient and permanent\u00a0cerebral ischemia (Gibson et al., 2006).<\/p>\n<p>Aside from preventing neuronal death, exogenous E2 replacement prior to stroke\u00a0was shown to attenuate behavioral deficits in ovariectomized female rats subjected to\u00a0GCI (Plamondon et al., 2006, Brann et al., 2007, Lebesgue et al., 2009). Furthermore,\u00a0exogenous E2 was shown to facilitate post-stroke recovery in mice by enhancing\u00a0neurogenesis in the dentate gyrus and subventricular zone after stroke, an effect that was\u00a0attenuated in estrogen receptor (ER) knockout (KO) mice and aromatase KO mice (Li et\u00a0al., 201 lb). As reviewed previously by our group and others, E2 has also been\u00a0demonstrated to afford protection in animal models of Parkinson\u2019s disease and<br \/>\nAlzheimer\u2019s disease (AD) (McCullough et al., 2003, Brann et al., 2007, Bourque et al.,\u00a02009, Pike et al., 2009). Finally, it should be mentioned that there are dissenting studies\u00a0in the literature, which found that E2 <em><i>increased <\/i><\/em>ischemic stroke damage in animal models\u00a0(Harukuni et al., 2001, Carswell et al., 2004a, Bingham et al., 2005, Gordon et al., 2005,\u00a0Theodorsson and Theodorsson, 2005, Yong et al., 2005). It is not completely clear as to\u00a0why these studies yielded a different result than the majority of studies in the literature,\u00a0but a recent review suggested that the difference could be due to use of E2 slow-release\u00a0pellets that yielded unexpectedly high circulating E2 levels (Strom et al., 2009).\u00a0Nevertheless, as a whole, research using animal models provides strong evidence for\u00a0endogenous and exogenous E2 as a neuroprotective agent,\u201d (pp. 85-86) (Scott et al.,\u00a02012<strong><b>).<\/b><\/strong><\/p>\n<p>&nbsp;<\/p>\n<p>Reference: Erin LeeAnn Scott. MOLECULAR MECHANISMS UNDERLYING ENHANCED RISK OF\u00a0NEUROLOGICAL DISEASE FOLLOWING PREMATURE MENOPAUSE<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Since Ed Hall and colleagues first discovered that female gerbils were relatively\u00a0protected from global cerebral ischemia, compared with their male counterparts, in the\u00a0early 1990s (Hall et al., 1991), gender differences [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[225,401],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/611"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=611"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/611\/revisions"}],"predecessor-version":[{"id":612,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/611\/revisions\/612"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=611"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=611"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=611"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}