Androgen receptor immunoreactivity in forebrain axons and dendrites in the rat

As members of the steroid receptor superfamily, androgen receptors (ARs) have been traditionally identified as transcription factors. In the presence of ligand, ARs reside in the nucleus, where, upon ligand binding, the receptors dimerize and bind to specific response elements in the promoter region of hormone-responsive genes. However, in this report, we describe the discovery that ARs are also present in axons and dendrites within the mammalian central nervous system. AR expression in axons was identified in the rat brain at the light microscopic level using two different antibodies directed against the N terminus of the AR protein and nickel intensified 3′-3′-diaminobenzidine, and also using fluorescence methods and confocal microscopy. This distribution was confirmed at the ultrastructural level. In addition, AR immunoreactivity was identified in small dendrites at the ultrastructural level. AR-immunoreactive axons were observed primarily in the cerebral cortex and were rare in regions where nuclear AR expression is abundant. The observation that ARs are present in axons and dendrites highlights the possibility that androgens play an important and novel extranuclear role in neuronal function.Peer Reviewe

Estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus is independent of estrogen receptor-beta

Estradiol regulates serotonin 1A(5-HT1A) receptor signaling. Since desensitization of 5-HT1A receptors may be an underlying mechanism by which selective serotonin reuptake inhibitors (SSRIs) mediate their therapeutic effects and combining estradiol with SSRIs enhances the efficacy of the SSRIs, it is important to determine which estrogen receptors are capable of desensitizating 5-HT1A receptor function. We previously demonstrated that selective activation of the estrogen receptor, GPR30, desensitizes 5-HT1A receptor signaling in rat hypothalamic paraventricular nucleus(PVN). However, since estrogen receptor beta(ERβ), is highly expressed in the PVN, we investigated the role of ERβ in estradiol-induced desensitization of 5-HT1A receptor signaling. We first showed that a selective ERβ agonist, diarylpropionitrile(DPN) has a 100-fold lower binding affinity than estradiol for GPR30. Administration of DPN did not desensitize 5-HT1A receptor signaling in rat PVN as demonstrated by agonist-stimulated hormone release. Second, we used a recombinant adenovirus containing ERβ siRNAs to decrease ERβ expression in the PVN. Reductions in ERβ did not alter the estradiol-induced desensitization of 5-HT1A receptor signaling in oxytocin cells. In contrast, in animals with reduced ERβ, estradiol administration, instead of producing desensitization, augmented the ACTH response to a 5-HT1A agonist. Combined with the results from the DPN treatment experiments, desensitization of 5-HT1A receptor signaling does not appear to be mediated by ERβ in oxytocin cells, but that ERβ, together with GPR30, may play a complex role in central regulation of 5-HT1A-mediated ACTH release. Determining the mechanisms by which estrogens induce desensitization may aid in the development of better treatments for mood disorders

Neuroprotection by estradiol

This review highlights recent evidence from clinical and basic science studies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may also enhance recovery from traumatic neurological injury such as stroke. Recent basic science studies show that not only does exogenous estradiol decrease the response to various forms of insult, but the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Thus, our view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission and enhanced neurogenesis. Some of the mechanisms underlying these effects are independent of the classically defined nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the classical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades through direct interactions with protein kinases or that estrogen receptor signaling may converge with signaling by other trophic molecules to confer resistance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include the optimal ligand and doses that can be used clinically to confer benefit without undue risk, modulation of neurotrophin and neurotrophin receptor expression, interaction of estrogen with regulated cofactors and coactivators that couple estrogen receptors to basal transcriptional machinery, interactions of estrogen with other survival and regeneration promoting factors, potential estrogenic effects on neuronal replenishment, and modulation of phenotypic choices by neural stem cells. Copyright (C) 2001 Elsevier Science Ltd.Peer Reviewe

In search of neuroprotective therapies based on the mechanisms of estrogens

Although estradiol is a neuroprotective factor, estrogen therapy in older women increases the risk of adverse cognitive outcomes and poses additional peripheral risks, requiring careful use of estrogenic compounds as treatments for neurodegenerative conditions or neural injury. Potential alternatives to estrogen therapy to promote neuroprotection might include treatment with molecules that are able to interact with estrogen receptors, with alternative mechanisms of action, or with molecules that induce local estradiol synthesis in the brain, or a combination of all. However, before considering the broad clinical applications, more basic research is required to clarify the mechamsms of action and potential risks of some of these estrogen-based treatments. © 2007 Future Drugs Ltd.Peer Reviewe

Oestradiol signalling in the hippocampus

Since the pioneering experiments demonstrating that oestradiol and related hormones can alter CNS responses other than the control of sexual behaviour, the hippocampus has been utilised as a valuable experimental model for deciphering the multiple roles of sex steroids in the mammalian brain. These roles include the regulation by oestradiol of neuronal and glial proliferation and survival throughout the lifespan, neuroprotection after insults, and the synaptic modulation essential for consolidation of learning and memory. Oestradiol exerts all these functions by various routes, including its receptor-mediated control of transcription, activation of intracellular signal transduction cascades, cross-talk with signalling mechanisms activated by other molecules, such as growth factors, allosteric modulation of membrane proteins, and its antioxidant properties. This review is focussed on the manner in which oestradiol exerts its effects within the hippocampus, and summarizes data on the distribution of known oestrogen receptors as well as how oestradiol modulates nuclear transcription and cell signalling events. ©2004 Bentham Science Publishers Ltd.Peer Reviewe

Cellular phenotype of androgen receptor-immunoreactive nuclei in the developing and adult rat brain

Androgen exposure during development and adulthood promotes cell-to-cell communication, modulates the size of specific brain nuclei, and influences hormone-dependent behavioral and neuroendocrine functions. Androgen action involves the activation of androgen receptors (AR). To elucidate the mechanisms involved in AR-mediated effects on forebrain development, double-label fluorescent immunohistochemistry and confocal microscopy were employed to identify the cellular phenotype of AR-immunoreactive (AR+) cells in the developing (embryonic day 20, postnatal days 0, 4, 10) and adult male rat forebrain. Sections were doubly labeled with antibodies directed against AR and one of the following: neurons (immature, nestin; mature, NeuN) or astrocytes [immature, vimentin; mature, glial fibrillary acidic protein (GFAP)] or mature oligodendrocytes (mGalC). In all brain regions examined, by far the majority of AR+ cells were neurons. In addition, small subsets of AR+ cells were identified as mature astrocytes (GFAP+) but only in specific brain regions at specific ages. AR+/GFAP+ cells were observed in the cerebral cortex but only in postnatal day 10 rats and in the arcuate nucleus of the hypothalamus but only in adult rats. Immature neurons, immature astrocytes, and oligodendrocytes were not AR+ at any age, in any region. Thus, both neurons and astrocytes in the male rat forebrain contain ARs, suggesting that androgens, via ARs, may exert effects on both cell types in an age- and region-dependent manner. © 2005 Wiley-Liss, Inc.Peer Reviewe

The role of glia in the hypothalamus: Implications for gonadal steroid feedback and reproductive neuroendocrine output

Neuron-to-glia, glia-to-neuron, and glia-to-glia communication are implicated in the modulation of neuronal activity and synaptic transmission relevant to reproduction. Glial cells play an important role in neuroendocrine regulation and participate in the sexual differentiation of neuronal connectivity of brain regions involved in the control of reproductive neuroenclocrine output. During puberty, modifications in the morphology and chemistry of astrocytes and tanycytes in the hypothalamus and median eminence influence the maturation of the neuronal circuits controlling the secretion of GnRH. During adult reproductive life, the glial cells participate in the transient remodeling of neuronal connectivity in the preoptic area, the arcuate nucleus, the median eminence, and other brain regions involved in the control of reproduction. Gonadal hormones regulate glial plasticity by direct and indirect effects and regulate various other endocrine signals, local soluble factors and adhesion molecules that also affect glial function and glia-to-neuron communication. The glial cells, therefore, are central to the coordination of endocrine and local inputs that bring about neural plasticity and adapt reproductive capacity to homeostatic signals. © 2008 Society for Reproduction and Fertility.Peer Reviewe

Neuroprotective actions of selective estrogen receptor modulators

Decreasing levels of sex hormones with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances. Extensive evidence from animal studies indicates that sex steroids, in particular estradiol, are neuroprotective. However, the potential benefits of estradiol therapy for the brain are counterbalanced by negative, life-threatening risks in the periphery. A potential therapeutic alternative to promote neuroprotection is the use of selective estrogen receptor modulators (SERMs), which may be designed to act with tissue selectivity as estrogen receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons. Finally, SERMs may promote the interaction of estrogen receptors with the neuroprotective signaling of growth factors, such as the phosphatidylinositol 3-kinase/glycogen synthase kinase 3 pathway. © 2009 Elsevier Ltd. All rights reserved.Peer Reviewe

Estrogen and brain vulnerability

Accumulated clinical and basic evidence suggests that gonadal steroids affect the onset and progression of several neurodegenerative diseases and schizophrenia, and the recovery from traumatic neurological injury such as stroke. Thus, our view on gonadal hormones in neural function must be broadened to include not only their function in neuroendocrine regulation and reproductive behaviors, but also to include a direct participation in response to degenerative disease or injury. Recent findings indicate that the brain up-regulates both estrogen synthesis and estrogen receptor expression at sites of injury. Genetic or pharmacological inactivation of aromatase, the enzyme involved in estrogen synthesis, indicates that the induction of this enzyme in the brain after injury has a neuroprotective role. Some of the mechanisms underlying the neuroprotective effects of estrogen may be independent of the classically defined nuclear estrogen receptors (ERs). Other neuroprotective effects of estrogen do depend on the classical nuclear ERs, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that non-classical ERs in the membrane or cytoplasm alter phosphorylation cascades, such as those involved in the signaling of insulin-like growth factor-I (IGF-I). Indeed, ERs and IGF-I receptor interact in the activation of PI3K and MAPK signaling cascades and in the promotion of neuroprotection. The decrease in estrogen and IGF-I levels with aging may thus result in an increased risk for neural pathological alterations after different forms of brain injury.Peer Reviewe