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Review
. 2009 May;27(3):240-9.
doi: 10.1055/s-0029-1216277. Epub 2009 Apr 28.

Estradiol is a potent protective, restorative, and trophic factor after brain injury

Candice M Brown  1 , Shotaro Suzuki, Karen A B Jelks, Phyllis M Wise
Affiliations
Review

Estradiol is a potent protective, restorative, and trophic factor after brain injury

Candice M Brown et al. Semin Reprod Med. 2009 May.

Abstract

Estrogens are a group of pleiotropic steroid hormones that exhibit diverse mechanisms of action in multiple physiologic systems. Over the past 30 years, biomedical science has begun to appreciate that endogenous estrogens and their receptors display important roles beyond the reproductive system. Our growing appreciation of novel, nonreproductive functions for estrogens has fundamentally contributed to our knowledge of their role in human health and disease. Recent findings from the Women's Health Initiative have caused clinicians and scientists to question whether estrogens are protective factors or risk factors. In light of the dichotomy between basic science and clinical studies, this review will attempt to reconcile differences between them. We will focus on studies from our laboratory and others highlighting the beneficial properties of the most abundant endogenous estrogen, 17beta-estradiol, using in vivo and in vitro models of cerebral ischemia and neuronal injury. These studies demonstrate that 17beta-estradiol powerfully protects the brain using multiple molecular mechanisms that promote: (1) decreased cell death, (2) increased neurogenesis, (3) an enhancement of neurotrophic support, and (4) the suppression of proinflammatory pathways.

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Figures

Figure 1
Figure 1. Physiological levels of estradiol protect against ischemic brain damage through ER α
(A) Representative coronal brain sections from oil- (Oil) and estradiol-(E) treated rat brains were collected at 1h, 4h, 24h over the evolution of injury and stained with hematoxylin and eosin. E2 exhibits substantial neuroprotection in the cerebral cortex compared to oil-treated controls by 24h. (B) Quantification of infarct volume over 24h reveals that E2 fails to protect at early stages of injury (1h, 4h, 8h) but provides significant neuroprotection against delayed cell death at the later stages of injury (16h, 24h) compared to oil-treated controls (*, p<0.001, n=7–11/experimental group at each time point). (C) Injury induces ERα mRNA in oil and E2 treated rat brains, as measured by in situ hybridization (p<0.004, n=3–5/group at each time point), but E2 amplifies the induction of ERα mRNA at earlier stages of injury (*, p<0.03) compared to oil-treated rats. Values represent mean ± SEM. (Reprinted with permission from: Dubal DB, Rau SW, Shughrue PJ, et al. Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERα in estradiol-mediated protection against delayed cell death. Endocrinology 2006;147:3076–3084.)
Figure 2
Figure 2. Differential regulation of cell death pathways by estradiol after MCAO injury
(A) E2 treatment significantly decreases the number of TUNEL-positive cells during the early (1–8h, #p<0.05) and late (16–24h, *p<0.05) stages of injury compared to oil-treated controls (n=8–10/group at each time point). (B) Estradiol reduces the caspase –mediated (120kDa) spectrin breakdown product at 4h after MCAO injury in the ischemic penumbra (*p<0.05, n=3–4/group at each time point). (C) Estradiol attenuates c-Fos immunoreactive (IR) cells in ischemic cortex during the secondary rise in number of c-Fos IR cells at 16–24h in comparison with oil treated counterparts (*p<0.05, n=6–10/group at each time point). Values represent mean ± SEM. (Reprinted with permission from: Rau SW, Dubal DB, Bottner M, Gerhold LM, Wise PM. Estradiol attenuates programmed cell death after stroke-like injury. Journal of Neuroscience 2003;23:11420–11426 and Rau S, Dubal D, Bottner M, Wise P. Estradiol differentially regulates c-Fos after focal cerebral ischemia. J Neurosci 2003;23(33):10487–10494)
Figure 3
Figure 3. Estradiol increases the number of newborn neurons in the subventricular zone (SVZ) after MCAO injury
(A, B) Confocal photomicrographs of BrdU+ cells (green) double-labeled with an early neuronal marker doublecortin (Dcx, red) in the ipsilateral SVZ of oil- (A) vs. E2- (B) treated mice at 96 h after MCAO injury. (C) E2 pretreatment significantly increased the number of BrdU/Dcx dual-labeled newbron neurons (*P = 0.0008, n = 6–7). (D, E) BrdU+ cells (green) did not co-label with markers for mature neurons (NeuN, red; D) or astrocyte (GFAP, red; E). CC, corpus callosum; STR, striatum. Values represent mean ± SEM. (Reprinted with permission from: Suzuki S, Gerhold LM, Bottner M, et al. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. J Comp Neurol 2005;500:1064–1075.)
Figure 4
Figure 4. Estradiol and inducible nitric oxide synthase are both neuroprotective after brain injury
(A) Estradiol reduces total infarct volume in WT mice (*, p<0.05,), but does not further suppress infarct size in iNOSKO mice. An effect of genotype was observed in iNOSKO oil-treated mice which were also protected during stroke compared to WT oil-treated mice (#, p<0.05, n=8–14 mice/treatment/genotype). (B) MIP1α/CCL3 was significantly suppressed by E2-treatment after MCAO injury in WT mice (*, p<0.05), while E2 provided no further suppression in iNOSKO mice compared to oil-treated controls. As with infarct volume, an effect of genotype was observed in iNOSKO oil-treated mice which were also protected during stroke compared to WT oil-treated mice (#, p<0.05, n = 7–12 mice/genotype/treatment). Values represent mean ± SEM. (Figure 4A reprinted with permission from: Brown CM, Dela Cruz CD, Yang E, Wise PM. Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury. Exp Neurol 2008;210:782–787)
Figure 5
Figure 5. Estradiol treatment increases synaptic cluster density and cluster size through ER α
(A–F) Double –label immuocytochemistry for NR1 (green) and vGlut1 (red); yellow in the superimposed images indicates colocalization (G) Estradiol treatment significantly increased the density of colocalized NR1 and vGlut1 clusters (48h, *p<0.0005, n=34 and 6d, *p<0.003, n=23). (H) Dual immunocytochemistry and confocal imaging revealed that exposure for 48h to E2 (10 nM; *p<0.027, n=22) and the ERa specific agonist, PPT (10 nM, *P<0.034, n=20), significantly increased colocalization of NR1 and vGlut1, thereby increasing the density of synaptic clusters. Values represent mean ± SEM. (Reprinted with permission from: Jelks KB, Wylie R, Floyd CL, McAllister AK, Wise P. Estradiol targets synaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons: critical role of estrogen receptor-alpha. J Neurosci 2007;27:6903–6913)
Figure 6
Figure 6. Estradiol protects UV-irradiated neurons from neuronal cell death
(A) Cortical and (B) hippocampal neurons pretreated with 10 nM and 100 nM E2 were significantly protected against UV irradiation compared to control cultures that were not exposed to E2. (*p<0.05, **p<0.01, n=14–20 wells/treatment). Values represent mean ± SEM.
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