Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol

Molecular Endocrinology and Oncology Research Center, Medical Center and Faculty of Pharmacy, Laval University, 2705 Laurier Boulevard, Sainte-Foy, Québec, Canada.
The Journal of Steroid Biochemistry and Molecular Biology (Impact Factor: 3.63). 03/2008; 108(3-5):327-38. DOI: 10.1016/j.jsbmb.2007.09.011
Source: PubMed


Clinical and experimental studies show a modulatory role of estrogens in the brain and suggest their beneficial action in mental and neurodegenerative diseases. The estrogen receptors ERalpha and ERbeta are present in the brain and their targeting could bring selectivity and reduced risk of cancer. Implication of ERs in the effect of estradiol on dopamine, opiate and glutamate neurotransmission is reviewed. The ERalpha agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ERbeta agonist DPN is inactive. Striatal DPN activity suggests implication of ERbeta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ERbeta knockout (ERKObeta) mice. Both ERalpha and ERbeta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ERalpha in striatal dopamine neuroprotection. ERKOalpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKObeta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists.

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    • "Estrogens, in particular 17β-estradiol (E2), play a fundamental role in regulating brain activity modulating neuronal expression of enzymes, receptors, structural proteins and synaptic plasticity and notably influencing cognition and behavior (Wong and Moss, 1992; Murphy and Segal, 1996; McEwen, 2002; Kramár et al., 2013). The E2 effects depend on genomic responses via nuclear receptors (Paech et al., 1997) and rapid non-genomic responses involving membrane receptors (ERα/β and GPER-1) (Kelly et al., 1976, 2002; Wong and Moss, 1992; Kelly and Levin, 2001; Qiu et al., 2003; Toran-Allerand, 2004; Revankar et al., 2005; Pedram et al., 2006; Morissette et al., 2008; Raz et al., 2008; Boulware and Mermelstein, 2009; Almey et al., 2012). The ERs may be also activated by extracellular "
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    ABSTRACT: 17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson’s disease.
    Frontiers in Cellular Neuroscience 05/2015; 9(192). DOI:10.3389/fncel.2015.00192 · 4.29 Impact Factor
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    • "Numerous studies have shown that E2 exerts powerful neuroprotective actions on multiple brain regions, including the cerebral cortex, hippocampus, striatum, basal forebrain, and cerebellum (Brown et al., 2009). E2 has also demonstrated a variety of actions on the brain by regulating spine density (Gould et al., 1990), synaptic number, and synthesis of neurotrophic factors (Sohrabji et al., 1995; Smith and McMahon, 2006; Morissette et al., 2008). In addition to its well-documented neuroregulatory effects, clinical investigations have provided the evidences that postmenopausal women are more vulnerable than young women to neurodegenerative diseases such as Alzheimer's (Boada et al., 2012; Mateos et al., 2012) and Parkinson's (Al Sweidi et al., 2012; Bourque et al., 2012) diseases, cerebral ischemic injury such as stroke, and memory or cognitive dysfunctions . "
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    ABSTRACT: Abstract 17β-Estradiol (E2), one of female sex hormones, has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the central cerebral ischemia, including stroke and neurodegenerative diseases. The cellular mechanisms that underlie these protective effects of E2 are uncertain because a number of different cell types express estrogen receptors in the central nervous system. Astrocytes are the most abundant cells in the central nervous system and provide structural and nutritive support of neurons. They interact with neurons by cross-talk, both physiologically and pathologically. Proper astrocyte function is particularly important for neuronal survival under ischemic conditions. Dysfunction of astrocytes resulting from ischemia significantly influences the responses of other brain cells to injury. Recent studies demonstrate that estrogen receptors are expressed in astrocytes, indicating that E2 may exert multiple regulatory actions on astrocytes. Cerebral ischemia induced changes in the expression of estrogen receptors in astrocytes. In the present review, we summarize the data in support of possible roles for astrocytes in the mediation of neuroprotection by E2 against cerebral ischemia.
    Reviews in the neurosciences 02/2014; 25(2). DOI:10.1515/revneuro-2013-0055 · 3.33 Impact Factor
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    • "The activation of these neurons promotes the release of dopamine and an increase in palatable food intake [25] [53] [54]. This stimulation in reward circuitry may occur through ERβ, given that this receptor is able to modulate the dopamine receptor and dopamine transporter in the striatum and accumbens nucleus [13] and it is probably the estradiol receptor more related to the ingestion of palatable foods [27]. Tamoxifen is known to have antagonist effects in ERβ [11], and this could explain the difference in chocolate intake between the tamoxifen and estradiol groups. "
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    ABSTRACT: Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer; however many women complain of weight gain during TAM treatment. The anorectic effects of estradiol (E) and TAM are well known, although the effects of E on the consumption of palatable food are controversial and there is no information regarding the effects of TAM on palatable food consumption. The aim of this study was to investigate the effects of chronic treatment with Estradiol and/or Tamoxifen on feeding behavior in ovariectomized rats exposed to standard chow and palatable foods (Froot Loops® or chocolate). Additionally, parameters such as body weight, uterine weight, lipid profile and plasma glucose were also measured. Wistar rats were ovariectomized (OVX) and subsequently injected (ip.) for 40 days with: E, TAM, E+TAM or vehicle (OVX and SHAM - controls). Behavioral tests were initiated 25 days after the start of treatment. Froot Loops® consumption was evaluated in a novel environment during 3 minutes. Standard chow intake was evaluated for two days and chocolate intake during 7 days in the home cage in a free choice model (chocolate or standard chow). Rats injected with E, TAM and E+TAM groups showed a reduction in body weight and standard chow intake, compared with control groups. With regard to palatable food intake, the E, TAM and E+TAM groups demonstrated increased consumption of Froot Loops®, compared with the SHAM and OVX groups. In contrast, all groups increased their consumption of chocolate, compared with standard chow; however the E group consumed more chocolate than the OVX, TAM and E+TAM groups. Despite these differences in chocolate consumption, all groups showed the same caloric intake during the chocolate exposure period; however the TAM and E+TAM groups presented decreased body weight. Treatment with estradiol and tamoxifen showed a favorable lipid profile with low levels of TC, LDL, LDL/HDL ratio and lower levels of plasma glucose. The E group presented high levels of TG and HDL, when compared with the TAM and E+TAM groups. Taken together, results suggest that TAM acted in an estrogen-like manner on the majority of parameters analyzed. However, tamoxifen acts in different manner depending on the type of palatable food and the exposure. In addition, the TAM group demonstrated weight loss, compared with other groups independently of the type of food presented (palatable food or standard chow), showing a low caloric efficiency.
    Physiology & Behavior 05/2013; 119. DOI:10.1016/j.physbeh.2013.05.026 · 2.98 Impact Factor
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