The Experts below are selected from a list of 765 Experts worldwide ranked by ideXlab platform

Robert J. Handa - One of the best experts on this subject based on the ideXlab platform.

  • Estrogen receptor β and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats.
    Physiology & behavior, 2014
    Co-Authors: Andrea E. Kudwa, Robert F. Mcgivern, Robert J. Handa
    Abstract:

    Abstract The hypothalamic–pituitary–adrenal (HPA) axis is activated in response to stressors and is controlled by neurons residing in the paraventricular nucleus of the hypothalamus (PVN). Although gonadal steroid hormones can influence HPA reactivity to stressors, the exact mechanism of action is not fully understood. It is known, however, that estrogen receptor β (ERβ) inhibits HPA reactivity and decreases anxiety-like behavior in rodents. Since ERβ is co-expressed with oxytocin (OT) in neurons of the PVN, an ERβ-selective agonist was utilized to test the whether ERβ decreases stress-induced HPA reactivity and anxiety-like behaviors via an OTergic pathway. Adult gonadectomized male and female rats were administered Diarylpropionitrile, or vehicle, peripherally for 5 days. When tested for anxiety-like behavior on the elevated plus maze (EPM), Diarylpropionitrile-treated males and females significantly increased time on the open arm of the EPM compared to vehicle controls indicating that ERβ reduces anxiety-like behaviors. One week after behavioral evaluation, rats were subjected to a 20 minute restraint stress. Treatment with Diarylpropionitrile reduced CORT and ACTH responses in both males and females. Subsequently, another group of animals was implanted with cannulae directed at the lateral ventricle. One week later, rats underwent the same protocol as above but with the additional treatment of intracerebroventricular infusion with an OT antagonist (des Gly-NH 2 d(CH 2 ) 5 [Tyr(Me) 2 , Thr 4 ] OVT) or VEH, 20 min prior to behavioral evaluation. OT antagonist treatment blocked the effects of Diarylpropionitrile on the display of anxiety-like behaviors and plasma CORT levels. These data indicate that ERβ and OT interact to modulate the HPA reactivity and the display of anxiety-like behaviors.

  • estrogen receptor β agonist Diarylpropionitrile biological activities of r and s enantiomers on behavior and hormonal response to stress
    Endocrinology, 2009
    Co-Authors: Michael J Weiser, Robert J. Handa
    Abstract:

    Estrogens have been shown to have positive and negative effects on anxiety and depressive-like behaviors, perhaps explained by the existence of two distinct estrogen receptor (ER) systems, ERα and ERβ. The ERβ agonist, Diarylpropionitrile (DPN) has been shown to have anxiolytic properties in rats. DPN exists as a racemic mixture of two enantiomers, R-DPN and S-DPN. In this study, we compared R-DPN and S-DPN for their in vitro binding affinity, ability to activate transcription in vitro at an estrogen response element, and in vivo endocrine and behavioral responses. In vitro binding studies using recombinant rat ERβ revealed that S-DPN has a severalfold greater relative binding affinity for ERβ than does R-DPN. Furthermore, cotransfection of N-38 immortalized hypothalamic cells with an estrogen response element-luc reporter and ERβ revealed that S-DPN is a potent activator of transcription in vitro, whereas R-DPN is not. Subsequently, we examined anxiety-like behaviors using the open-field test and elevate...

  • postovariectomy weight gain in female rats is reversed by estrogen receptor α agonist propylpyrazoletriol
    American Journal of Obstetrics and Gynecology, 2008
    Co-Authors: Iga N Wegorzewska, Katy Walters, Michael J Weiser, Danette F Cruthirds, Emily Ewell, Darwin O Larco, Robert J. Handa
    Abstract:

    Objective The objective of this study was to distinguish the role of specific estrogen receptors (ERs), ERα and ERβ, on body weight regulation using a rat model of weight gain subsequent to menopause. Study Design Ovariectomized rats were utilized as the animal model to simulate the postmenopause weight gain. The rats were ovariectomized and subcutaneously injected daily with vehicle, estradiol-17β (E2), propylpyrazoletriol (PPT; ERα agonist) and Diarylpropionitrile (DPN; ERβ agonist). To further control for the possible effect of estrogen secreted from adrenals, a second experiment was conducted during which the rats were adrenalectomized and ovariectomized. Results Ovariectomy significantly increased ( P P Conclusion These results suggest that the activation of ERα is important in regulating body weight.

  • Postovariectomy weight gain in female rats is reversed by estrogen receptor alpha agonist, propylpyrazoletriol.
    American journal of obstetrics and gynecology, 2008
    Co-Authors: Iga N Wegorzewska, Katy Walters, Michael J Weiser, Danette F Cruthirds, Emily Ewell, Darwin O Larco, Robert J. Handa
    Abstract:

    The objective of this study was to distinguish the role of specific estrogen receptors (ERs), ERalpha and ERbeta, on body weight regulation using a rat model of weight gain subsequent to menopause. Ovariectomized rats were utilized as the animal model to simulate the postmenopause weight gain. The rats were ovariectomized and subcutaneously injected daily with vehicle, estradiol-17beta (E2), propylpyrazoletriol (PPT; ERalpha agonist) and Diarylpropionitrile (DPN; ERbeta agonist). To further control for the possible effect of estrogen secreted from adrenals, a second experiment was conducted during which the rats were adrenalectomized and ovariectomized. Ovariectomy significantly increased (P < .05) body weight, whereas treatment of ovariectomized rats with E2 and PPT, but DPN decreased (P < .05) body weight. The results from the second study with ovariectomized/adrenalectomized rats were consistent with the first experiment. These results suggest that the activation of ERalpha is important in regulating body weight.

  • The Androgen 5α-Dihydrotestosterone and Its Metabolite 5α-Androstan-3β, 17β-Diol Inhibit the Hypothalamo–Pituitary–Adrenal Response to Stress by Acting through Estrogen Receptor β-Expressing Neurons in the Hypothalamus
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2006
    Co-Authors: Trent D. Lund, Laura R. Hinds, Robert J. Handa
    Abstract:

    Estrogen receptor β (ERβ) and androgen receptor (AR) are found in high levels within populations of neurons in the hypothalamus. To determine whether AR or ERβ plays a role in regulating hypothalamo–pituitary–adrenal (HPA) axis function by direct action on these neurons, we examined the effects of central implants of 17β-estradiol (E2), 5α-dihydrotestosterone (DHT), the DHT metabolite 5α-androstan-3β, 17β-diol (3β-diol), and several ER subtype-selective agonists on the corticosterone and adrenocorticotropin (ACTH) response to immobilization stress. In addition, activation of neurons in the paraventricular nucleus (PVN) was monitored by examining c-fos mRNA expression. Pellets containing these compounds were stereotaxically implanted near the PVN of gonadectomized male rats. Seven days later, animals were killed directly from their home cage (nonstressed) or were restrained for 30 min (stressed) before they were killed. Compared with controls, E2 and the ERα-selective agonists moxestrol and propyl-pyrazole-triol significantly increased the stress induced release of corticosterone and ACTH. In contrast, central administration of DHT, 3β-diol, and the ERβ-selective compound Diarylpropionitrile significantly decreased the corticosterone and ACTH response to immobilization. Cotreatment with the ER antagonist tamoxifen completely blocked the effects of 3β-diol and partially blocked the effect of DHT, whereas the AR antagonist flutamide had no effect. Moreover, DHT, 3β-diol, and Diarylpropionitrile treatment significantly decreased restraint-induced c-fos mRNA expression in the PVN. Together, these studies indicate that the inhibitory effects of DHT on HPA axis activity may be in part mediated via its conversion to 3β-diol and subsequent binding to ERβ.

Irshad H. Chaudry - One of the best experts on this subject based on the ideXlab platform.

  • 17β-Estradiol's Salutary Effects on Splenic Dendritic Cell Functions Following Trauma-Hemorrhage are Mediated via
    2015
    Co-Authors: Estrogen Receptor-α, Martin G. Schwacha, Takao Suzuki, Mashkoor A. Choudhry, Takashi Kawasaki, Irshad H. Chaudry
    Abstract:

    Although 17β-estradiol administration following trauma-hemorrhage attenuates Kupffer cell, splenic and peritoneal macrophage functions, it remains unknown whether 17β-estradiol has any salutary effects on splenic dendritic cell (DC) functions and if so, whether such effects are mediated via the estrogen receptors (ER). We hypothesized that 17β-estradiol administration following trauma-hemorrhage has salutary effects on splenic DC functions. Male C3H/HeN (6-8 weeks) mice were randomly assigned to sham operation or trauma-hemorrhage. Trauma-hemorrhage was induced by midline laparotomy and ∼90 min of hemorrhagic shock (blood pressure [BP] 35 mmHg), followed by fluid resuscitation (4 × the shed blood volume in the form of Ringer's lactate). Estrogen receptor (ER)-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist Diarylpropionitrile (DPN; 5μg/ kg), 17β-estradiol (50 μg/kg), or vehicle (10 % DMSO) was injected subcutaneously during resuscitation. Two hrs later, the mice were sacrificed, splenic DCs were isolated and the changes in their apoptosis, co-stimulating factors and MHC class II expression, ability to produce cytokines, and antigen presentation capacity were measured. Apoptosis of splenic DC increased following trauma-hemorrhage; however, 17β-estradiol administration after trauma-hemorrhage normalized th

  • Estradiol’s Salutary Effects on Keratinocytes Following Trauma-Hemorrhage Are Mediated by Estrogen Receptor (ER)-α and ER-β
    Molecular Medicine, 2008
    Co-Authors: Fariba Moeinpour, Mashkoor A. Choudhry, Luiz F. Poli De Figueiredo, Kirby I. Bland, Irshad H. Chaudry
    Abstract:

    Although administration of 17β-estradiol (estrogen) following trauma-hemorrhage attenuates the elevation of cytokine production and mitogen-activated protein kinase (MAPK) activation in epidermal keratinocytes, whether the salutary effects of estrogen are mediated by estrogen receptor (ER)-α or ER-β is not known. To determine which estrogen receptor is the mediator, we subjected C3H/HeN male mice to trauma-hemorrhage (2-cm midline laparotomy and bleeding of the animals to a mean blood pressure of 35 mmHg and maintaining that pressure for 90 min) followed by resuscitation with Ringer’s lactate (four times the shed blood volume). At the middle of resuscitation we subcutaneously injected ER-α agonist propyl pyrazole triol (PPT; 5 µg/kg), ER-β agonist Diarylpropionitrile (DPN; 5 µg/kg), estrogen (50 µg/kg), or ER antagonist ICI 182,780 (150 µg/kg). Two hours after resuscitation, we isolated keratinocytes, stimulated them with lipopolysaccharide for 24 h (5 µg/mL for maximum cytokine production), and measured the production of interleukin (IL)-6, IL-10, IL-12, and TNF-α and the activation of MAPK. Keratinocyte cytokine production markedly increased and MAPK activation occurred following trauma-hemorrhage but were normalized by administration of estrogen, PPT, and DPN. PPT and DPN administration were equally effective in normalizing the inflammatory response of keratinocytes, indicating that both ER-α and ER-β mediate the salutary effects of estrogen on keratinocytes after trauma-hemorrhage.

  • Estradiol's salutary effects on keratinocytes following trauma-hemorrhage are mediated by estrogen receptor (ER)-alpha and ER-beta.
    Molecular medicine (Cambridge Mass.), 2008
    Co-Authors: Fariba Moeinpour, Mashkoor A. Choudhry, Luiz F. Poli De Figueiredo, Kirby I. Bland, Irshad H. Chaudry
    Abstract:

    Although administration of 17beta-estradiol (estrogen) following trauma-hemorrhage attenuates the elevation of cytokine production and mitogen-activated protein kinase (MAPK) activation in epidermal keratinocytes, whether the salutary effects of estrogen are mediated by estrogen receptor (ER)-alpha or ER-beta is not known. To determine which estrogen receptor is the mediator, we subjected C3H/HeN male mice to trauma-hemorrhage (2-cm midline laparotomy and bleeding of the animals to a mean blood pressure of 35 mmHg and maintaining that pressure for 90 min) followed by resuscitation with Ringer's lactate (four times the shed blood volume). At the middle of resuscitation we subcutaneously injected ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), ER-beta agonist Diarylpropionitrile (DPN; 5 microg/kg), estrogen (50 microg/kg), or ER antagonist ICI 182,780 (150 microg/kg). Two hours after resuscitation, we isolated keratinocytes, stimulated them with lipopolysaccharide for 24 h (5 microg/mL for maximum cytokine production), and measured the production of interleukin (IL)-6, IL-10, IL-12, and TNF-alpha and the activation of MAPK. Keratinocyte cytokine production markedly increased and MAPK activation occurred following trauma-hemorrhage but were normalized by administration of estrogen, PPT, and DPN. PPT and DPN administration were equally effective in normalizing the inflammatory response of keratinocytes, indicating that both ER-alpha and ER-beta mediate the salutary effects of estrogen on keratinocytes after trauma-hemorrhage.

  • Systematic analysis of the salutary effect of estrogen on cardiac performance after trauma-hemorrhage.
    Shock (Augusta Ga.), 2008
    Co-Authors: Jun-te Hsu, Jianguo Chen, Wen Hong Kan, Martin G. Schwacha, Irshad H. Chaudry
    Abstract:

    Although 17"-estradiol (estrogen) and estrogen receptor (ER) agonist administration after trauma- hemorrhage improves cardiac function, it remains unknown what the optimal estrogen or ER agonist dosage is to elicit this beneficial effect. To study this, the dose-dependent effects of estrogen, propylpyrazole triol (ER-! agonist), and Diarylpropionitrile (DPN; ER-" agonist) on heart performance (+dP/dt) were determined in sham rats and in experimental animals at the time of maximal bleedout (MBO) or at 2 h after trauma-hemorrhage. The results showed that estrogen and DPN induced dose-dependent increases in the maximal rate of left ventricular pressure increase (+dP/dt) in all groups, whereas propylpyrazole triol was ineffective at all doses. The maximal dose and the 50% effective dose of DPN were approximately 100-fold lower than those of estrogen. The half-life of estrogen in plasma was approximately 25 min in sham and MBO groups. A positive correlation between the estrogen-induced increase in +dP/dt and survival in MBO rats were observed. These results collectively suggest that the salutary effects of estrogen on cardiac performance are dose- dependent and mediated via ER-". KEYWORDS—Hemorrhagic shock, +dP/dt, Diarylpropionitrile, propylpyrazole triol

  • Salutary effects of 17β-estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-α
    American journal of physiology. Cell physiology, 2007
    Co-Authors: Takao Suzuki, Tomoharu Shimizu, Ya-ching Hsieh, Mashkoor A. Choudhry, Irshad H. Chaudry
    Abstract:

    Although 17β-estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17β-estradiol are mediated via estrogen receptor (ER)-α or ER-β. Moreover, it is unknown which signaling pathways are involved in 17β-estradiol's salutary effects. Utilizing an ER-α- or ER-β-specific agonist, we examined the role of ER-α and ER-β in E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NF-κB, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NF-κB, and AP-1. Male rats underwent trauma-hemorrhage (mean arterial pressure 40 mmHg for 90 min) and fluid resuscitation. ER-α agonist propyl pyrazole triol (PPT; 5 μg/kg), ER-β agonist Diarylpropionitrile (DPN; 5 μg/kg), 17β-estradiol (50 μg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, sple...

Cheryl A. Frye - One of the best experts on this subject based on the ideXlab platform.

  • antiseizure effects of 3α androstanediol and or 17β estradiol may involve actions at estrogen receptor β
    Epilepsy & Behavior, 2009
    Co-Authors: Cheryl A. Frye, Allicia Ryan, Madeline E. Rhodes
    Abstract:

    Abstract Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects. Some of these effects may be mediated by T’s metabolites. T is metabolized to 3α-androstanediol (3α-diol). T, but not 3α-diol, binds androgen receptor. We investigated effects of 3α-diol (1 mg/kg, SC) and/or an androgen receptor blocker (flutamide 10 mg, SC), 1 hour prior to administration of pentylenetetrazol (85 mg/kg, IP). Juvenile male rats administered 3α-diol had less seizure activity than those administered vehicle. Flutamide had no effects. T is aromatized to 17β-estradiol (E 2 ), which, like 3α-diol, acts at estrogen receptors (ERs). Selective estrogen receptor modulators that favor ERα (propyl pyrazole triol, 17α-E 2 ) or ERβ (Diarylpropionitrile, coumestrol, 3α-diol), or both (17β-E 2 ), were administered (0.1 mg/kg, SC) to juvenile male rats 1 hour before pentylenetetrazol. Estrogens with activity at ERβ, but not those selective for ERα, produced antiseizure effects. Actions at ERβ may underlie some antiseizure effects of T’s metabolites.

  • Antiseizure effects of 3α-androstanediol and/or 17β-estradiol may involve actions at estrogen receptor β
    Epilepsy & Behavior, 2009
    Co-Authors: Cheryl A. Frye, Allicia Ryan, Madeline E. Rhodes
    Abstract:

    Abstract Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects. Some of these effects may be mediated by T’s metabolites. T is metabolized to 3α-androstanediol (3α-diol). T, but not 3α-diol, binds androgen receptor. We investigated effects of 3α-diol (1 mg/kg, SC) and/or an androgen receptor blocker (flutamide 10 mg, SC), 1 hour prior to administration of pentylenetetrazol (85 mg/kg, IP). Juvenile male rats administered 3α-diol had less seizure activity than those administered vehicle. Flutamide had no effects. T is aromatized to 17β-estradiol (E 2 ), which, like 3α-diol, acts at estrogen receptors (ERs). Selective estrogen receptor modulators that favor ERα (propyl pyrazole triol, 17α-E 2 ) or ERβ (Diarylpropionitrile, coumestrol, 3α-diol), or both (17β-E 2 ), were administered (0.1 mg/kg, SC) to juvenile male rats 1 hour before pentylenetetrazol. Estrogens with activity at ERβ, but not those selective for ERα, produced antiseizure effects. Actions at ERβ may underlie some antiseizure effects of T’s metabolites.

  • Antiseizure effects of 3α-androstanediol and/or 17β-estradiol may involve actions at estrogen receptor β
    Epilepsy & behavior : E&B, 2009
    Co-Authors: Cheryl A. Frye, Allicia Ryan, Madeline E. Rhodes
    Abstract:

    Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects. Some of these effects may be mediated by T's metabolites. T is metabolized to 3alpha-androstanediol (3alpha-diol). T, but not 3alpha-diol, binds androgen receptor. We investigated effects of 3alpha-diol (1 mg/kg, SC) and/or an androgen receptor blocker (flutamide 10 mg, SC), 1 hour prior to administration of pentylenetetrazol (85 mg/kg, IP). Juvenile male rats administered 3alpha-diol had less seizure activity than those administered vehicle. Flutamide had no effects. T is aromatized to 17beta-estradiol (E(2)), which, like 3alpha-diol, acts at estrogen receptors (ERs). Selective estrogen receptor modulators that favor ERalpha (propyl pyrazole triol, 17alpha-E(2)) or ERbeta (Diarylpropionitrile, coumestrol, 3alpha-diol), or both (17beta-E(2)), were administered (0.1 mg/kg, SC) to juvenile male rats 1 hour before pentylenetetrazol. Estrogens with activity at ERbeta, but not those selective for ERalpha, produced antiseizure effects. Actions at ERbeta may underlie some antiseizure effects of T's metabolites.

  • Adult female wildtype, but not oestrogen receptor β knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or Diarylpropionitrile
    Journal of psychopharmacology (Oxford England), 2008
    Co-Authors: Alicia A. Walf, Carolyn J. Koonce, Cheryl A. Frye
    Abstract:

    AbstractStudies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17β-oestradiol (E2), as well as administration of E2-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E2 is important to improve future E2-based therapeutics. An important question is whether effects of E2 or SERMs for mood regulation act at the α or β isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E2-based therapies may involve actions at ERα, rather than ERβ. In the present study, whether there are sex differences in depression-like behaviour of adult mice (experiment 1), and the effects of natural fluctuations in E2 (experiment 2), or administration of E2 or a SERM that has higher affinity for ERβ than for ERα (Diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERβ knockout (βERKO) mice were investigated. Results of this study supported our hypotheses that...

  • Estradiol or Diarylpropionitrile Decrease Anxiety-Like Behavior of Wildtype, but Not Estrogen Receptor Beta Knockout, Mice
    Behavioral neuroscience, 2008
    Co-Authors: Alicia A. Walf, Carolyn J. Koonce, Cheryl A. Frye
    Abstract:

    Among adults, anxiety-related disorders are diagnosed in at least twice the number of women than men (Seeman, 1997). This trend continues into aging, when it becomes even more marked following decline in estradiol (E2) secretion from the ovaries around menopause (Jenkins, 1987; Wittchen & Hoyer, 2001). As such, the role of E2 in both the etiology and treatment of anxiety disorders is of interest. An increased incidence of anxiety symptoms coincident with a decline and/or rapid change in E2 levels as occurs in both young (premenstrually, postpartum) and older (menopausal, post-menopausal) women suggests a role of E2 in the etiology of anxiety disorders (Bebbington, Hurry, Tennant, Sturt & Wing, 1981; Bloch, Daly & Rubinow, 2003; Jenkins, 1987; Rubinow & Schmidt, 1995). E2-based therapies have been used for many years to treat physiological symptoms associated with menopause, such as hot flashes, night sweats, genital dryness, as well as mental symptoms, such as cognition, anxiety, and mood. Although there are some disparities in results (mainly attributed to E2 regimen utilized, age, and/or length of ovarian cessation before initiation of treatment), several studies in perimenopausal and/or postmenopausal women demonstrate that E2 therapies can reduce anxiety or improve mood (Schmidt, Nieman, Danaceau, Tobin, Roca, et al., 2000; Sherwin, 1991; Sherwin & Gelfand, 1985; reviewed in Walf & Frye, 2006). However, limitations of E2-based therapies due to their proliferative effects in breast and/or uterus have dampened enthusiasm for their use as treatments for anxiety/mood disturbances. Some of these limitations in the clinical studies of E2 for affective processes have been explored using animal models. A post-pubertal sex difference, favoring males, in anxiety-like behaviors of rodents is less apparent among adult females during proestrus, coincident with an increase in E2 levels (Frye, Petralia & Rhodes, 2000; Palanza, 2001). Female mice spend twice as long on the open arms of the elevated plus maze during proestrus compared to diestrus (Galeeva & Tuohimaa, 2001). Compared to male rats or female rats in diestrus, proestrous rats spend more time on the open arms of the elevated plus maze, more time in social interaction with a conspecific, and less time freezing in response to footshock in a defensive freezing paradigm (Frye, Petralia & Rhodes, 2000, Mora, Dussaubat & Diaz-Veliz, 1996). Cessation of ovarian secretion of E2, achieved via ovariectomy (ovx), abolishes this effect among young rodents and administration of E2 decreases anxiety-like behavior across a variety of tasks in both rats and mice (Frye, Petralia & Rhodes, 2000; Nomikos & Spyraki, 1988; reviewed in Walf & Frye, 2006). However, these effects are dose-dependent, such that only moderate increases in E2 levels, which produce proestrous-like concentrations, decrease anxiety-like behavior (Walf & Frye, 2005a). In these studies, rodents were young adults that were acutely administered E2 within a few weeks of ovx because the length of E2 treatment may influence the anxiolytic-like effects of E2 (Walf & Frye, 2006). Fewer studies have investigated the age and/or time-dependent effects of E2 for anxiety-like behavior, but there is some data in support of this using cognitive function as a measure. E2 improved cognitive behavior of younger vs. older rats more effectively following long-term ovx; however, older rats responded more favorably than did younger rats to E2 treatment that produced cyclical fluctuations in E2 rather than steady chronic E2 levels (Markowska & Savonenko, 2002). Thus, E2 treatment parameters may determine the magnitude of E2’s anxiety-reducing effects. Another important consideration to make regarding the efficacy of E2 for its anxiolytic-like effects is the mechanism of E2 for these effects. E2 has actions at two distinct ERs isoforms, which are regionally distributed throughout the body and brain, in addition to having distinct N-terminal regions and being encoded by different genes (reviewed in Zhao, Dahlman-Wright, & Gustafsson, 2008). It is likely that some of the regional differences in ERα vs, ERβ distribution in the brain may confer specific functional effects of E2 acting via these receptor isoforms. Although ERα is predominant in the ventromedial hypothalamus, which is related to E2’s facilitatory actions for female rodent sexual responding, ERβ is predominant in limbic and/or stress-responsive regions of the brain, such as the hippocampus, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus (Shughrue, Lane & Merchenthaler, 1997; Shughrue, Scrimo & Merchenthaler, 1998). Thus, it may be that E2 has actions to alter affective behavior of rodents in part through ERβ. In our laboratory and others, the functional effects of E2 via actions at ERβ for anxiety behavior have been investigated using both ERβ knockdown and ERβ activation approaches. First, ERβ knockdown occurring over a long period of time, such as is observed in mice with an ERβ knockout mutation (βERKO mice), increases anxiety-like and depression-like behavior, compared to that observed in wildtype (WT) mice. This effect was not reversed with subcutaneous E2 treatment (Imwalle, Gustafsson & Rissman, 2005; Krezel, Dupont, Krust, Chambon & Chapman, 2001; Rocha, Fleischer, Schaeffer, Rohrer & Hickey, 2005; Walf & Frye, 2006; Walf, Koonce, & Frye, 2008a). Second, anxiety-like and depression-like behavior of ovx rats intracerebroventricularly administered ERβ antisense oligonucleotides coincident with acute E2-priming was increased, compared to administration of scrambled or ERa antisense oligonucleotides (Walf, Ciriza, Garcia-Segura & Frye, 2008). Third, behavioral effects of selective estrogen receptor modulators (SERMs) that have greater affinity for ERβ support the notion that ERβ may be important for E2’s anxiety-reducing effects. Lifelong administration of phytoestrogens with a greater affinity for ERβ than ERα, such as genistein and daidzein, in the diet of male and female rats decreases anxiety-like behavior in the elevated plus maze (Lund & Lephart, 2001). As well, acute (44–48 hour) subcutaneous administration of coumestrol and Diarylpropionitrile (DPN), which are SERMs with greater affinity for ERβ than ERα, decrease anxiety-like and depression-like behavior of ovx and male rats compared to administration of vehicle or ERα–selective SERMs (Lund, Rovis, Chung & Handa, 2005; Walf & Frye, 2005b; Walf, Rhodes & Frye, 2004). To investigate further the specificity of E2 and DPN’s effects for anxiety behavior, WT and βERKO mice were administered vehicle, E2, or DPN and, 44 hours later, performance effects were compared. We hypothesized that WT, but not βERKO, mice would be responsive to the effects of E2 and DPN to decrease anxiety-like behavior.

Adel K. El-naggar - One of the best experts on this subject based on the ideXlab platform.

  • Biological Role of Estrogen Receptor β in Salivary Gland Adenocarcinoma Cells
    Clinical Cancer Research, 2006
    Co-Authors: Kazufumi Ohshiro, Suresh K. Rayala, Michelle D. Williams, Rakesh Kumar, Adel K. El-naggar
    Abstract:

    Purpose: This study is intended to investigate the biological role of estrogen receptor (ER) nongenomic signaling in salivary gland adenocarcinoma cells that predominantly express ERβ. Experimental Design: Salivary gland adenocarcinoma cell lines HSG and HSY were used to study the effect of Diarylpropionitrile and estrogen on the nongenomic signaling of ERβ, cytoskeletal remodeling, and cell motility. Results: We found that Diarylpropionitrile and estrogen triggered rapid activation of the extracellular signal-regulated kinase 1/2 (ERK), Src, and focal adhesion kinase signaling pathways. Estrogen stimulation also induced long cytoplasmic extensions, filopodia formation, and abnormal outgrowths in both HSG and HSY cells. We further observed that ligand-induced migration of these cells was blocked by the pure antiestrogen ICI 182780 and the mitogen-activated protein/ERK kinase inhibitor PD98059, indicating that estrogen-induced cell migration is mediated by the activation of ERβ nongenomic signaling. Conclusion: These results clearly showed that ERβ nongenomic signaling is active in salivary gland cells and has a biological role in migration, presumably via the stimulation of ERK1/2. In future, the findings of this study might have clinical importance as several ERβ-selective agonists are currently being available, and these could potentially be used for therapeutic targeting of ERβ-positive salivary tumors.

  • Biological role of estrogen receptor beta in salivary gland adenocarcinoma cells.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006
    Co-Authors: Kazufumi Ohshiro, Suresh K. Rayala, Michelle D. Williams, Rakesh Kumar, Adel K. El-naggar
    Abstract:

    This study is intended to investigate the biological role of estrogen receptor (ER) nongenomic signaling in salivary gland adenocarcinoma cells that predominantly express ERbeta. Salivary gland adenocarcinoma cell lines HSG and HSY were used to study the effect of Diarylpropionitrile and estrogen on the nongenomic signaling of ERbeta, cytoskeletal remodeling, and cell motility. We found that Diarylpropionitrile and estrogen triggered rapid activation of the extracellular signal-regulated kinase 1/2 (ERK), Src, and focal adhesion kinase signaling pathways. Estrogen stimulation also induced long cytoplasmic extensions, filopodia formation, and abnormal outgrowths in both HSG and HSY cells. We further observed that ligand-induced migration of these cells was blocked by the pure antiestrogen ICI 182780 and the mitogen-activated protein/ERK kinase inhibitor PD98059, indicating that estrogen-induced cell migration is mediated by the activation of ERbeta nongenomic signaling. These results clearly showed that ERbeta nongenomic signaling is active in salivary gland cells and has a biological role in migration, presumably via the stimulation of ERK1/2. In future, the findings of this study might have clinical importance as several ERbeta-selective agonists are currently being available, and these could potentially be used for therapeutic targeting of ERbeta-positive salivary tumors.

John A Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.

  • Estrogen Receptor-Selective Agonists Modulate Learning in Female Rats in a Dose- and Task-Specific Manner
    Endocrinology, 2015
    Co-Authors: Samantha L. Pisani, John A Katzenellenbogen, Steven L. Neese, Susan L. Schantz, Donna L. Korol
    Abstract:

    Estrogens are well known for their enhancing effects on hippocampus-sensitive cognition. However, estrogens can also impair learning and memory, particularly the acquisition of striatum-sensitive tasks. These cognitive shifts appear to be mediated through local estrogen receptor (ER) activation in each neural structure, but little information is known regarding which specific ER subtypes drive the opposing effects on learning. Elucidating the mnemonic roles of discrete ER subtypes is essential for predicting how treatments with distinct ER pharmacology such as drugs, hormone therapies, and phytoestrogen supplements affect cognitive abilities in and thus the daily lives of the women who take them. The present study examined the effects of the ERα-selective compound propyl pyrazole triol and the ERβ-selective compounds Diarylpropionitrile and Br-ERb-041 on place and response learning in young adult female rats. Long-Evans rats were ovariectomized and maintained on phytoestrogen-free chow for 3 weeks before behavioral training, with treatments administered via subcutaneous injection 48 and 24 hours before testing. A dose-response paradigm was used, with each compound tested at 4 different doses in separate groups of rats. Propyl pyrazole triol, Diarylpropionitrile, and Br-ERb-041 all enhanced place learning and impaired response learning, albeit with distinct dose-response patterns for each compound and task. These results are consistent with the detection of ERα and ERβ in the hippocampus and striatum and suggest that learning is modulated via activation of either ER subtype.

  • ESR1 and ESR2 differentially regulate daily and circadian activity rhythms in female mice.
    Endocrinology, 2014
    Co-Authors: S. E. Royston, John A Katzenellenbogen, Norio Yasui, A. G. Kondilis, S. V. Lord, Megan M. Mahoney
    Abstract:

    Estrogenic signaling shapes and modifies daily and circadian rhythms, the disruption of which has been implicated in psychiatric, neurologic, cardiovascular, and metabolic disease, among others. However, the activational mechanisms contributing to these effects remain poorly characterized. To determine the activational impact of estrogen on daily behavior patterns and differentiate between the contributions of the estrogen receptors ESR1 and ESR2, ovariectomized adult female mice were administered estradiol, the ESR1 agonist propylpyrazole triol, the ESR2 agonist Diarylpropionitrile, or cholesterol (control). Animals were singly housed with running wheels in a 12-hour light, 12-hour dark cycle or total darkness. Estradiol increased total activity and amplitude, consolidated activity to the dark phase, delayed the time of peak activity (acrophase of wheel running), advanced the time of activity onset, and shortened the free running period (τ), but did not alter the duration of activity (α). Importantly, ac...

  • Pharmacokinetics of the estrogen receptor subtype-selective ligands, PPT and DPN: quantification using UPLC-ES/MS/MS.
    Journal of pharmaceutical and biomedical analysis, 2012
    Co-Authors: Estatira Sepehr, John A Katzenellenbogen, Samantha L. Pisani, Donna L. Korol, Marketa Lebl-rinnova, Meagan K. Mann, Mona I. Churchwell, Daniel R. Doerge
    Abstract:

    Estrogen receptor (ER) subtype specific agonists, Diarylpropionitrile (DPN) for ERβ and propylpyrazoletriol (PPT) for ERα, are pharmacological probes used frequently to define mechanisms for estrogen actions in vitro and in vivo. Quantitative analytical methodology was developed and validated for DPN and PPT, based on synthetic stable labeled analogs (DPN-d4 and PPT-d5) using isotope dilution liquid chromatographic tandem electrospray mass spectrometric detection. The validated method produced high sensitivity, with detection limits of 0.04–0.07 ng/ml serum. Serum pharmacokinetics were evaluated in Long-Evans rats following a single subcutaneous injection (2 mg/kg bw) of both compounds. The role of Phase II metabolism was evaluated using β-glucuronidase and arylsulfatase hydrolysis to measure total DPN and PPT in addition to the parent compounds. The pharmacokinetic properties of DPN and PPT reported could facilitate experimental designs requiring specified levels of receptor occupancy for quantitative comparisons of ER subtype specificities for natural and synthetic estrogens in vivo.

  • Diarylpropionitrile dpn enantiomers synthesis and evaluation of estrogen receptor β selective ligands
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Vincent Carroll, Kathryn E Carlson, M Jeyakumar, John A Katzenellenbogen
    Abstract:

    Two estrogen receptor (ER) subtypes, ERα and ERβ, mediate the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activa...

  • Diarylpropionitrile (DPN) Enantiomers: Synthesis and Evaluation of Estrogen Receptor β-Selective Ligands
    2012
    Co-Authors: Vincent M. Carroll, Kathryn E Carlson, M Jeyakumar, John A Katzenellenbogen
    Abstract:

    Two estrogen receptor (ER) subtypes, ERα and ERβ, mediate the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activate these subtypes differentially, have proved to be useful in elucidating which actions of estrogens proceed through ERα vs ERβ. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ERβ selective ligand that we developed, is a chiral molecule, but it has been studied almost exclusively as the racemic mixture (rac-DPN, 1). Herein we report the development of an efficient enantioselective synthesis of the two isomers, R-DPN (3) and S-DPN (2), and we have compared the in vitro ligand binding affinities, coactivator binding affinities, recruitment potencies, and cellular transcriptional potencies of these isomers. Both enantiomers show a very high affinity and potency preference for ERβ over ERα, typically in the range of 80–300-fold. Although the enantioselectivity is only modest (3–4-fold), the R-enantiomer is the higher affinity and more potent isomer. While ERβ can be effectively and selectively stimulated by rac-DPN or by either R-DPN or S-DPN, R-DPN might be the preferred member of this isomeric series for biological studies of ERβ function