Aromatase, the enzyme that synthesises oestrogens from androgen precursors, is expressed in the brain, where it has been classically associated with the regulation of neuroendocrine events and ...behaviours linked with reproduction. Recent findings, however, have revealed new unexpected roles for brain aromatase, indicating that the enzyme regulates synaptic activity, synaptic plasticity, neurogenesis and the response of neural tissue to injury, and may contribute to control nonreproductive behaviours, mood and cognition. Therefore, the function of brain aromatase is not restricted to the regulation of reproduction as previously thought.
Abstract Estradiol biosynthesis is catalyzed by the enzyme aromatase, the product of the CYP19A1 gene. Aromatase is expressed in the brain, where it is involved not only in the control of ...neuroendocrine events and reproduction, but also in the regulation of neural development, synaptic plasticity and cell survival. In this review we summarize the existing data related with the detection of aromatase in human brain, with particular emphasis in the so-called “non-primary reproductive” areas. Besides hypothalamus, amygdala and preoptic/septal areas, aromatase is expressed in certain regions of basal forebrain, cerebral cortex, hippocampus, thalamus, cerebellum and brainstem of the human brain. Aromatase in human brain is produced by neurons, but there is also an astrocyte subpopulation that constitutively expresses the enzyme. The use of different methodological approaches, including the in vivo analysis by positron emission tomography of human subjects, has permitted to draw a general map of human brain aromatase, but the detailed distribution map is still far to be completed. On the other hand, despite the fact that there is only one aromatase protein, there are multiple mRNA transcripts that differ in the 5'-untranslated region, where regulatory elements reside. To date, some of the aromatase transcripts characteristic of cerebral cortex, as well as of human cell lines of neural origin, have been identified. This characteristic may confer tissue or even region-specific regulation of the expression and therefore it is conceivable to develop selective aromatase modulators to regulate the expression of the enzyme in the human brain. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
Estradiol and some selective estrogen receptor modulators (SERMs) are neuroprotective in a variety of experimental models of neurodegeneration, reduce the inflammatory response of glial cells, reduce ...anxiety and depression, promote cognition and modulate synaptic plasticity in the hippocampus of rodents. In this study we have assessed whether estradiol and two SERMs currently used in clinics, tamoxifen and raloxifene, affect medial prefrontal cortex function and morphology. Rats were ovariectomized and six days later some animals received a subcutaneous injection of the estrogenic compounds. In a first experiment animals were treated with estradiol benzoate or sesame oil vehicle. In a second experiment animals received raloxifene, tamoxifen or dimethyl sulfoxide as vehicle. Twenty four hours after the pharmacological treatment, animals were challenged to solve an allocentric working memory paradigm in a “Y” maze. Twenty trials consisting of a study phase and a test phase were conducted according to a delayed match-to-sample procedure in a single one-day session. Animals that were not submitted to behavioral test were used for Golgi analysis of the prefrontal cortex. Rats treated with estradiol benzoate, tamoxifen or raloxifene performed better in the Y maze and showed a significant increase in the numerical density of dendritic spines in secondary apical dendrites of layer III pyramidal neurons from the prelimbic/infralimbic prefrontal cortex, compared to their respective control groups. These findings suggest that estradiol, tamoxifen and raloxifene improve prefrontal cortex-related cognitive performance and modulate prefrontal cortex morphology in ovariectomized rats.
► Estradiol treatment improves allocentric working memory in ovariectomized rats. ► Estradiol treatment increases dendritic spine density in ovariectomized rats. ► Tamoxifen improves allocentric working memory in ovariectomized rats. ► Raloxifene improves allocentric working memory in ovariectomized rats. ► Both tamoxifen and raloxifene increase spine density in ovariectomized rats.
Abstract Studies in experimental animals have revealed important roles of neuroactive steroids in the control of central nervous system functions during physiological and pathological conditions, ...suggesting that they may represent good candidates for the development of neuroprotective strategies for neurodegenerative and psychiatric disorders. Even if the characterization of the roles played by neuroactive steroids in humans is still at the beginning, several data are already available showing that they may be synthesized within the human CNS. Among the different enzymes, a prominent role is dedicated to aromatase that synthesizes estradiol whose neuroprotective effects have been described in experimental animals. Neuroactive steroid levels are modified by neurodegenerative conditions (i.e. Alzheimer's and Parkinson's diseases, multiple sclerosis) or in other mental diseases (i.e. schizophrenia), and may have an important role in physiological conditions, as the reorganization of grey and white matter during human puberty and adolescence or as a consequence of emotional responses. The interaction of some neuroactive steroids (i.e., allopregnanolone and isopregnanolone) with GABA-A receptor is particularly important in mood disorders. The presumptive role of estradiol and progesterone in neuroprotection is here discussed by comparing contradictory data that have been collected in humans. In conclusion, the state of the art of our knowledge of the role of neuroactive steroids in the normal and pathological human brain suggests several lines of future therapeutic developments in the treatments of neurological, neurodegenerative and affective disorders. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
Perinatal maternal malnutrition is related to altered growth of tissues and organs. The nervous system development is very sensitive to environmental insults, being the hippocampus a vulnerable ...structure, in which altered number of neurons and granular cells has been observed. Moreover, glial cells are also affected, and increased expression of proinflammatory mediators has been observed. We studied the effect of Glucagon-like peptide-1 receptor (GLP-1R) agonists, liraglutide, which have very potent metabolic and neuroprotective effects, in order to ameliorate/prevent the glial alterations present in the hippocampus of the pups from mothers with food restriction during pregnancy and lactation (maternal perinatal food restriction-MPFR).
Pregnant Sprague-Dawley rats were randomly assigned to 50% food restriction (FR; n = 12) or ad libitum controls (CT, n = 12) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant FR and CT rats were treated with liraglutide (100 μg/kg) or vehicle. At postnatal day 21 and before weaning, 48 males and 45 females (CT and MPFR) were sacrificed. mRNA expression levels of interleukin-1β (IL1β), interleukin-6 (IL-6), nuclear factor-κβ, major histocompatibility complex-II (MHCII), interleukin 10 (IL10), arginase 1 (Arg1), and transforming growth factor (TGFβ) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 and GFAP-immunoreactivity were assessed by immunocytochemistry.
The mRNA expression IL1β, IL6, NF-κB, and MHCII increased in the hippocampus of male but not in female pups from MPFR. In addition, there was an increase in the percentage of GFAP and Iba1-immupositive cells in the dentate gyrus compared to controls, indicating an inflammatory response in the brain. On the other hand, liraglutide treatment prevented the neuroinflammatory process, promoting the production of anti-inflammatory molecules such as IL10, TGFβ, and arginase 1, and decreasing the number and reactivity of microglial cells and astrocytes in the hippocampus of male pups.
Therefore, the GLP-1 analog, liraglutide, emerges as neuroprotective drug that minimizes the harmful effects of maternal food restriction, decreasing neuroinflammation in the hippocampus in a very early stage.
Brain expression of the enzyme P450‐aromatase has been studied extensively. Subsequent to the aromatisation hypothesis having established brain aromatase as a key factor to convert gonadal ...testosterone to oestradiol, several studies have investigated the regulation of aromatase during the critical period of brain sexual differentiation. We review previous and recent findings concerning regulation of aromatase. The role of gonadal hormones, sex chromosome genes and neurosteroids is analysed in terms of their contribution to aromatase expression, as well as implications for the organisational effect of steroids during development.
Neuroglobin (Ngb), so named after its initial discovery in brain neurones, has received great attention as a result of its neuroprotective effects both in vitro and in vivo. Recently, we demonstrated ...that, in neurones, Ngb is a 17β‐oestradiol (E2) inducible protein that is pivotal for hormone‐induced anti‐apoptotic effects against H2O2 toxicity. The involvement of Ngb in other brain cell populations, as well as in other neuroprotective effects of E2, is completely unknown at present. We demonstrate Ngb immunoreactivity in reactive astrocytes located in the proximity of a penetrating cortical injury in vivo and the involvement of Ngb in the E2‐mediated anti‐inflammatory effect in primary cortical astrocytes. Upon binding to oestrogen receptor (ER)β, E2 enhances Ngb levels in a dose‐dependent manner. Although with a lesser degree than E2, the pro‐inflammatory stimulation with lipopolysaccharide (LPS) also induces the increase of Ngb protein levels via nuclear factor‐(NF)κB signal(s). Moreover, a negative cross‐talk between ER subtypes and NFκB signal(s) has been demonstrated. In particular, ERα‐activated signals prevent the NFκB‐mediated Ngb increase, whereas LPS impairs the ERβ‐induced up‐regulation of Ngb. Therefore, the co‐expression of both ERα and ERβ is pivotal for mediating E2‐induced Ngb expression in the presence of NFκB‐activated signals. Interestingly, Ngb silencing prevents the effect of E2 on the expression of inflammatory markers (i.e. interleukin 6 and interferon γ‐inducible protein 10). Ngb can be regarded as a key mediator of the different protective effects of E2 in the brain, including protection against oxidative stress and the control of inflammation, both of which are at the root of several neurodegenerative diseases.
The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and humans via hypothalamic actions. We discovered expression of ghrelin in a previously uncharacterized group of neurons ...adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These neurons send efferents onto key hypothalamic circuits, including those producing neuropeptide Y (NPY), Agouti-related protein (AGRP), proopiomelanocortin (POMC) products, and corticotropin-releasing hormone (CRH). Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Using electrophysiological recordings, we found that ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH). We propose that at these sites, release of ghrelin may stimulate the release of orexigenic peptides and neurotransmitters, thus representing a novel regulatory circuit controlling energy homeostasis.
Significant levels of neuroactive steroids are still detected in the nervous system of rodents after the removal of peripheral steroidogenic glands. However, the influence of the plasma levels of ...gonadal steroids on the levels of neuroactive steroids in the nervous system has not so far been clarified in detail. Accordingly, by liquid chromatography tandem mass spectrometry, we have analysed the levels of neuroactive steroids in the sciatic nerve, in three central nervous system (CNS) regions (i.e. cerebellum, cerebral cortex and spinal cord) and in the plasma of male and female animals. The levels present in gonadally intact animals were compared with those present in short‐ and long‐term gonadectomised animals. We observed that: (i) changes in neuroactive steroid levels in the nervous system after gonadectomy do not necessarily reflect the changes in plasma levels; (ii) long‐term gonadectomy induces changes in the levels of neuroactive steroids in the peripheral nervous system (PNS) and the CNS that, in some cases, are different to those induced by short‐term gonadectomy; (iii) the effect of gonadectomy on neuroactive steroid levels is different between the PNS and the CNS and within different CNS regions; and (iv) the effects of gonadectomy on neuroactive steroid levels in the nervous system show sex differences. Altogether, these observations indicate that the nervous system adapts its local levels of neuroactive steroids in response to changes in gonadal hormones with sex and regional specificity and depending on the duration of the peripheral modifications.
Steroidogenic machinery in the adult rat colon Diviccaro, S.; Giatti, S.; Borgo, F. ...
The Journal of steroid biochemistry and molecular biology,
October 2020, 2020-10-00, 20201001, Letnik:
203
Journal Article
Recenzirano
•Adult rat colon expresses molecules involved in the early steps of steroidogenesis.•Synthesis and metabolism of sex steroids also occurred.•Levels of pregnenolone and progesterone and testosterone ...metabolites are higher in colon than in plasma.•Higher levels of 3α-diol were detected in the colon in comparison with cerebral cortex.
Gastrointestinal function is known to be regulated by steroid molecules produced by the gonads, the adrenal glands and the gut microbiota. However, we have a limited knowledge on the functional significance of local steroid production by gastrointestinal tract tissue. On this basis, we have here evaluated, as a first methodological approach, the expression of steroidogenic molecules and the local levels of key steroids in the male rat colon. Our findings indicate that the colon tissue expresses molecules involved in the early steps of steroidogenesis and in the consecutive synthesis and metabolism of steroid hormones, such as progesterone, testosterone and 17β-estradiol. In addition, the levels of the steroid hormone precursor pregnenolone and the levels of active metabolites of progesterone and testosterone, such as dihydroprogesterone, tetrahydroprogesterone, dihydrotestosterone and 17β-estradiol, were higher in colon than in plasma. Higher levels of the androgen metabolite 3α-diol were detected in the colon in comparison with another non-classical steroidogenic tissue, such as the cerebral cortex. These findings suggest the existence of local steroid synthesis and metabolism in the colon, with the production of active steroid metabolites that may impact on the activity of the enteric nervous system and on the composition of the gut microbiota.
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