Selective Estrogen Receptor Modulator Effects in the Rat Brain

Zhou, Wenxia; Koldzic-Zivanovic, Nina; Clarke, Charlotte H.; Beun, R. de; Wassermann, Karsten; Bury, Paul S.; Cunningham, Kathryn A.; Thomas, Mary L.

doi:10.1159/000048218

Cited by 60 publications

(25 citation statements)

References 42 publications

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“…These experimental data suggest that estrogenic therapies may have a beneficial effect in slowing the rate of progression of Parkinson’s disease, an idea also supported by epidemiological evidence [14, 15, 16, 17, 18, 26]. However, a caveat to realizing the therapeutic utility of this approach is the potential for unwanted side effects that result from the actions of estrogens outside the CNS [18, 27]. Thus, it will be important to determine the mechanism of the neuroprotective effect of estrogen, as a first step towards developing new compounds that avoid this liability.…”

Section: Discussionmentioning

confidence: 94%

“…However, it is unclear at present which of these receptors is being targeted. ERβ, but not ERα, is expressed in the substantia nigra in rodents [27, 31]. Interestingly, however, Dubal et al [32]presented data suggesting that the interaction of 17β-estradiol with the ERα, and not the ERβ receptor, mediates the neuroprotective effect of the steroid in an ischemia model.…”

Section: Discussionmentioning

confidence: 99%

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Repeated Estradiol Treatment Prevents MPTP-Induced Dopamine Depletion in Male Mice

Ramirez

Liu

Menniti³

2003

Neuroendocrinology

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Epidemiological data suggest that the steroid hormone 17β-estradiol plays an important role in protecting the brain from neurodegenerative processes, including that causing the loss of dopamine (DA) neurons in Parkinson’s disease. Determining the mechanisms of neuroprotection in experimental systems may facilitate the development of estrogenic therapies for these diseases. The present study sought to further investigate the mechanism of the neuroprotective effect of 17β-estradiol in a murine model of Parkinson’s disease, i.e. 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal DA depletion. Consistent with previous findings, 17β-estradiol was found to inhibit MPTP-induced DA depletion under a dosing regimen (repeated daily administration) that mimicked physiological levels of the steroid. However, high doses of the steroid administered repeatedly or acutely failed to inhibit toxicity, as did 17α- estradiol. These data suggest that the neuroprotective effect of 17β-estradiol was mediated through an interaction with one of the nuclear estrogen receptors, and is not the result of an antioxidant action. In order to realize the therapeutic potential of the neuroprotective effect of 17β-estradiol for Parkinson’s disease, it will be necessary to identify synthetic estrogen receptor modulators that lack the activity of the steroid on peripheral tissue. In this study, raloxifene failed to mimic the neuroprotective effect of 17β-estradiol against MPTP toxicity. Thus, exploration of new compounds with different pharmacological and/or physiochemical properties is warranted.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Repeated Estradiol Treatment Prevents MPTP-Induced Dopamine Depletion in Male Mice

Ramirez

Liu

Menniti³

2003

Neuroendocrinology

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“…Estrogenic compounds reduce the extent of the injury, the sensorimotor and working memory deficits, and reactive astrogliosis after TBI [123, 124, 133, 170-175]. For instance, estradiol has been shown to reduce intracranial pressure, oedema formation and BBB permeability in female rats after TBI [176].…”

Section: Neuroprotective Actions Of Estrogenic Compounds After Tbimentioning

confidence: 99%

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

et al. 2018

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Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.

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“…Reports analyzing the action of estrogen in vivo on SERT uptake sites and mRNA levels are inconclusive. Increases, decreases, and no change have been reported (Attali et al, 1997;Bethea et al, 1998;Krajnak et al, 2003;McQueen et al, 1997;Mendelson et al, 1993, Zhou et al, 2002. Discrepancies in these studies may be explained by variability in the treatment paradigm used, such as the time elapsed between ovariectomy and estrogen treatment, the duration of estrogen treatment, and the brain region evaluated.…”

Section: Introductionmentioning

confidence: 99%

Impact of Ovarian Hormones on the Modulation of the Serotonin Transporter by Fluvoxamine

Benmansour

Piotrowski

Altamirano

et al. 2008

Neuropsychopharmacol

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Most preclinical studies examining the mechanism(s) of action of antidepressants are carried out using male animals. Blockade of serotonin transporter (SERT) function by selective serotonin reuptake inhibitors (SSRIs) is the initial event that triggers a not completely understood process that results in clinical improvement in depression. To investigate whether there are differences in the ability of SSRIs to inhibit the SERT between male and female rats at different phases of the estrous cycle, clearance of locally applied serotonin (5-HT) was measured by in vivo chronoamperometry. Local application of the SSRI, fluvoxamine, directly into the CA3 area of hippocampus increased significantly 5-HT clearance time parameters in male rats and female rats in estrus or diestrus, but not in proestrus. The contribution of ovarian steroids to this result was investigated in ovariectomized (OVX) rats treated with estradiol benzoate (EB) and/or progesterone (P). In OVX-control rats, fluvoxamine increased clearance time parameters, whereas EB and/or P treatment blocked this effect, consistent with what was seen in female rats in proestrus. This effect was gender-specific, since treatment of castrated rats with EB/ P had no effect on the ability of fluvoxamine to slow 5-HT clearance. The time course of hormonal effects showed that 1-60 min after local application of 17-b-estradiol (E 2 ) into the CA3 region of OVX rats, fluvoxamine had no effect on clearance time of 5-HT. E 2 -BSA mimicked E 2 's effects at 10 min but not at 60 min. Pretreatment with estrogen receptor antagonists blocked the effects of E 2 . The finding that acutely both estradiol and progesterone can inhibit the ability of an SSRI to slow the clearance of 5-HT, may have important implications for the use of SSRIs in women.

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Selective Estrogen Receptor Modulator Effects in the Rat Brain

Cited by 60 publications

References 42 publications

Repeated Estradiol Treatment Prevents MPTP-Induced Dopamine Depletion in Male Mice

Repeated Estradiol Treatment Prevents MPTP-Induced Dopamine Depletion in Male Mice

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

Impact of Ovarian Hormones on the Modulation of the Serotonin Transporter by Fluvoxamine

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