Selective Estrogen Receptor Modulators Regulate Dendritic Spine Plasticity in the Hippocampus of Male Rats

González-Burgos, Ignacio; Rivera-Cervantes, M.C.; Velázquez-Zamora, Dulce A.; Feria‐Velasco, Alfredo; Garcia-Segura, Luis Miguel

doi:10.1155/2012/309494

Cited by 37 publications

(21 citation statements)

References 85 publications

(44 reference statements)

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“…While functional outcomes were not addressed in the current study, the findings nevertheless suggest that SERMs may have the capacity to enhance structural and behavioral recovery following ischemic brain injury. In support of this possibility, both raloxifene and tamoxifen have been reported to acutely enhance spine density in the hippocampus and prefrontal cortex of normal non-ischemic male rats, an effect that was correlated with enhanced allocentric working memory [12, 13]. The molecular mechanisms underlying raloxifene and tamoxifen regulation of sine density in the cerebral cortex is currently unclear.…”

Section: Discussionmentioning

confidence: 99%

“…However, a number of studies suggest that tamoxifen and raloxifene can have neuroprotective effects in vitro or in vivo against neurological insults or in neurological disorders [1–11]. Additionally, both tamoxifen and raloxifene have also been shown to enhance memory, cognition, and synaptic plasticity in various experimental studies [12, 13]. However the mechanisms underlying the beneficial neural effects of SERMs are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia

Khan

Wakade

Sevilla

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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Selective estrogen receptor modulators (SERMs) have been reported to enhance synaptic plasticity and improve cognitive performance in adult rats. SERMs have also been shown to induce neuroprotection against cerebral ischemia and other CNS insults. In this study, we sought to determine whether acute regulation of neurogenesis and spine remodeling could be a novel mechanism associated with neuroprotection induced by SERMs following cerebral ischemia. Toward this end, ovariectomized adult female rats were either implanted with pellets of 17β-estradiol (estrogen) or tamoxifen, or injected with raloxifene. After one week, cerebral ischemia was induced by the transient middle-cerebral artery occlusion (MCAO) method. Bromodeoxyuridine (BrdU) was injected to label dividing cells in brain. We analyzed neurogenesis and spine density at day-1 and day-5 post MCAO. In agreement with earlier findings, we observed a robust induction of neurogenesis in the ipsilateral subventricular zone (SVZ) of both the intact as well as ovariectomized female rats following MCAO. Interestingly, neurogenesis in the ipsilateral SVZ following ischemia was significantly higher in estrogen and raloxifene-treated animals compared to placebo-treated rats. In contrast, this enhancing effect on neurogenesis was not observed in tamoxifen-treated rats. Finally, both SERMs, as well as estrogen significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia. Taken, together these results reveal a profound structural remodeling potential of SERMs in the brain following cerebral ischemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia

Khan

Wakade

Sevilla

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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“…Raloxifene, a second-generation selective estrogen receptor modulator, is approved for use in the treatment of osteoporosis in postmenopausal women and for breast cancer in women and can have beneficial effects on brain function including increased cortical plasticity. 39 , 40 Studies have reported that raloxifene at a daily dose of 120 mg preserved neural activity during a memory challenge in healthy aging men 41 and preserved cognition in postmenopausal women. 42 Recent clinical trials and case reports have shown that adjunctive raloxifene at 60 or 120 mg is beneficial for the treatment of positive, negative and general psychopathology symptoms in postmenopausal women with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia

et al. 2015

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There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

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“…Estradiol and testosterone were shown to regulate dendritic length and the density of spines in the spinal cord nucleus of the bulbocavernosus (SNB), VMH, ARH, medial amygdala, striatum, cortex and hippocampus ([5, 17, 26, 34, 45, 48, 50, 69, 70, 79–81, 115, 147, 151]; see Luine et al and MacLusky et al, this volume). The most dramatic effects of estradiol on neuronal number and morphology occur during development, but significant steroid regulation of dendritic structure also occurs in adulthood.…”

Section: Introductionmentioning

confidence: 99%

Membrane-initiated estradiol actions mediate structural plasticity and reproduction

Micevych

Christensen

2012

Frontiers in Neuroendocrinology

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Over the years, our ideas about estrogen signaling have greatly expanded. In addition to estradiol having direct nuclear actions that mediate transcription and translation, more recent experiments have demonstrated membrane-initiated signaling. Both direct nuclear and estradiol membrane signaling can be mediated by the classical estrogen receptors, ERα and ERβ, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ERα has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ERα is a ligand-gated transcription factor and not a typical membrane receptor, trafficking to the cell membrane requires post-translational modifications. Two necessary modifications are palmitoylation and association with caveolins, a family of scaffolding proteins. In addition to their role in trafficking, caveolin proteins also serve to determine ERα interactions with metabotropic glutamate receptors (mGluRs). It is through these complexes that ERα, which cannot by itself activate G proteins, is able to initiate intracellular signaling. Various combinations of ERα-mGluR interactions have been demonstrated throughout the nervous system from hippocampus to striatum to hypothalamus to dorsal root ganglion (DRG) in both neurons and astrocytes. These combinations of ER and mGluR allow estradiol to have both facilitative and inhibitory actions in neurons. In hypothalamic astrocytes, the estradiol-mediated release of intracellular calcium stores regulating neurosteroid synthesis requires ERα-mGluR1a interaction. In terms of estradiol regulation of female sexual receptivity, activation of ERα-mGluR1a signaling complex leads to the release of neurotransmitters and alteration of neuronal morphology. This review will examine estradiol membrane signaling (EMS) activating a limbic-hypothalamic lordosis regulating circuit, which involves ERα trafficking, internalization, and modifications of neuronal morphology in a circuit that underlies female sexual receptivity.

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Selective Estrogen Receptor Modulators Regulate Dendritic Spine Plasticity in the Hippocampus of Male Rats

Cited by 37 publications

References 85 publications

Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia

Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia

Membrane-initiated estradiol actions mediate structural plasticity and reproduction

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