Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice in vitro was reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice. 125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and 125I-CRH binding, CRH-R1 mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1beta (IL-1beta) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R1 mRNA levels in WT mice, but not in TG mice, whereas IL-1beta produced a decrease in these mRNA levels in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression characteristics of disorders such as major depression.
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PMID:Reduced activity of hypothalamic corticotropin-releasing hormone neurons in transgenic mice with impaired glucocorticoid receptor function. 957 Aug 18

We investigated the effectiveness of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) administered into the brain to induce anorexia in acutely fasted Wistar rats allowed to refeed. We also assayed for changes in mRNA levels of IL-1 system components, TNF-alpha, TGF-beta1, glycoprotein 130 (gp 130), leptin receptor (OB-R), pro-opiomelanocortin (POMC), neuropeptide Y (NPY), glucocorticoid receptor (GR), and CRF receptor (CRF-R) in selected brain regions. The data show that LPS and MDP induced anorexia differentially during refeeding. LPS-induced anorexia was of a stronger magnitude and duration than that of MDP. RNase protection assays showed that LPS and MDP significantly increased the expression of IL-1beta, IL-1 receptor type I, and TNF-alpha mRNAs in the cerebellum, hippocampus, and hypothalamus; LPS was more potent in all cases. MDP treatment, on the other hand, induced a stronger increase in hypothalamic levels of IL-1 receptor antagonist (IL-1Ra) and TGF-beta1 mRNAs relative to LPS. In addition, competitive RT-PCR analysis showed that LPS induced an eleven-fold increase in IL-1alpha mRNA in the hypothalamus relative to vehicle. These findings suggest that LPS and MDP mediate anorexia through different cytokine mechanisms. A stronger up-regulation of anti-inflammatory cytokines (IL-1Ra and TGF-beta1) mRNA expression by MDP may be involved in the weaker MDP-induced anorexia relative to LPS. No significant changes were observed in the peptide components examined except for an up-regulation in cerebellar gp 130 mRNA and down-regulation of hypothalamic GR mRNA expression in response to LPS or MDP. This study shows that LPS and MDP induce anorexia in fasted rats allowed to refeed, and suggests an important role for endogenous cytokine-cytokine interactions.
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PMID:Lipopolysaccharide (LPS)- and muramyl dipeptide (MDP)-induced anorexia during refeeding following acute fasting: characterization of brain cytokine and neuropeptide systems mRNAs. 962 98

Synthetic and naturally occurring steroids exert a variety of neural effects that include modulation of nocturnal sleep. The present study focuses on the effect of progesterone receptor (PR) activation on the nocturnal sleep electroencephalogram (EEG) in male volunteers. As a PR ligand, the synthetic progesterone megestrol was used, which has the advantage over progesterone in that it is not metabolized into other steroid compounds which could cloud the progesterone-mediated effects through their own neuroactive properties. Nine healthy male volunteers were investigated in a prospective single-blind randomized study design. They received either placebo tablets or megestrol acetate dosages of 160, 320 or 480 mg at 14.00 h and 19.00 h. Blood samples were drawn half-hourly from 22.00 h until 07.00 h. After 320 mg megestrol, plasma adrenocorticotropin secretion was lower and growth hormone secretion was higher than after 160 mg and 480 mg megestrol or placebo. Similarly, the reduction in the relative amount of rapid eye movement sleep was most pronounced after 320 mg. Thus, progesterone receptor activation, as reflected by the sleep EEG and associated pituitary hormone secretion, follows a nonlinear U-shape dose dependency of a well-defined PR ligand, which may explain the unresolved inconsistencies of neuroendocrine progesterone effects to date. Moreover, employing a CV1 cell line, contransfected with a human glucocorticoid receptor expression vector and a reporter gene-based detection system for transcriptional activity, revealed that a PR agonist such as megestrol may also activate glucocorticoid receptors. This may account for some of the neuroendocrine effects of megestrol and other progestins.
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PMID:Sleep endocrine effects of megestrol acetate in healthy men. 974 90

Twenty-four hours of maternal deprivation have been shown to have immediate and long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis. In the first experiment the influence of such a maternal deprivation period (pnd 11-12) on basal and stress-induced ACTH and CORT levels 4 and 8 days following reunion was investigated. The results revealed a suppression of the ACTH response in the previously deprived animals which was not reflected in the CORT response. In the second experiment these persistent effects were studied in animals deprived during different stages of development. Deprivation early in development (pnd 3-4) produced an animal with a hyperreactive ACTH response whereas deprivation later (pnd 7-8, pnd 11-12) resulted in a hyporeactive ACTH response to stress at pnd 20. To study further the possible mechanisms leading to these different ACTH responses, we used in situ hybridization to investigate hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) gene expression and corticotropin-releasing hormone (CRH) and GR mRNA levels in the paraventricular nucleus of the hypothalamus (PVN) of these 20-day old animals. Permanent changes in hippocampal GR mRNA were seen only in the later deprived pups, whereas GR mRNA was reduced in the PVN in all deprived pups. In conclusion, maternal deprivation during the neonatal period produces alterations in the ACTH response to a mild stress and sustained changes in GR transcript levels. The direction and magnitude of these effects are dependent upon the age at which maternal deprivation is experienced.
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PMID:Persistent, but Paradoxical, Effects on HPA Regulation of Infants Maternally Deprived at Different Ages. 978 49

After 24 hr of maternal deprivation, significant elevations in ACTH and the naturally occurring glucocorticoid corticosterone (CORT) are observed during the stress-hyporesponsive period. The deprived pups also showed in the paraventricular nucleus (PVN) a marked increase of stress-induced c-fos mRNA and a reduction of corticotropin-releasing hormone (CRH) and glucocorticoid receptor (GR) mRNA; in hippocampal CA1, a reduction of the mineralocorticoid receptor (MR) and GR was observed. Here, we examined whether these changes are reversed by (1) preventing the elevations of CORT characteristic for the 11-d-old deprived pups by administering the synthetic glucocorticoid dexamethasone (DEX); or (2) reinstating some aspects of maternal behavior. The pups were either (1) left undisturbed, (2) stroked, or (3) stroked and episodically fed by cheek cannulation. At postnatal day 12, peripheral and neural stress markers were measured. Nondeprived animals served as controls. Experiment 1 demonstrates that although CORT was kept low by DEX, the central effects on CORT receptors, CRH, and c-fos mRNA were still present, except for MR in hippocampal CA1. Experiment 2 shows that stroking alone prevented the stress-induced rise in ACTH and c-fos mRNA and in the reduction in CRH and MR mRNA. In pups that were fed and stroked, CORT and GR mRNA resembled nondeprived controls. In conclusion, the changes in peripheral endocrine responses and in the brain cannot be attributed to the effect of elevated CORT concentrations, which are characteristic of the maternally deprived neonate. However, reinstating some components of the dams' nurturing behavior can reverse the effects evoked by maternal deprivation.
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PMID:Maternal deprivation effect on the infant's neural stress markers is reversed by tactile stimulation and feeding but not by suppressing corticosterone. 982 70

Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibit resistance to the normal feedback effects of glucocorticoids on proopiomelanocortin (POMC) gene expression. This glucocorticoid resistance is typically complete, although some tumors show only relative glucocorticoid resistance in the clinical setting. The molecular mechanisms responsible for these clinical pathophysiologic observations are unknown, but might include glucocorticoid receptor defects or aberrant expression of enzymes or transporters that exclude glucocorticoids from access to their intracellular receptors. We examined whether ACTH-producing non-pituitary tumor cells might express 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the principal 'gatekeeper' enzyme known to metabolize glucocorticoids. 11Beta-HSD mRNA and enzyme activity were assessed in DMS-79 cells, a line derived from an ACTH-producing small cell lung cancer. RT-PCR studies showed expression of mRNA encoding 11beta-HSD2 but not 11beta-HSD1 in DMS-79 cells. Control human fibroblasts expressed predominantly 11beta-HSD1 but also had detectable 11beta-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11beta-HSD2 mRNA. Whole cell assays in DMS-79 cells revealed 11beta-HSD activity with a Km for cortisol of 26.1 +/- 9.0 nM and Vmax of 57.0 +/- 5.9 pmol/h/mg protein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11beta-HSD activity with a Km for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibited to 7% of baseline by addition of 10 microM glycyrrhetinic acid. Dexamethasone (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11beta-HSD2. While DMS-79 cells harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors.
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PMID:Expression of 11beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer. 988 91

By means of double immunohistochemical techniques and a nonradioisotopic in situ hybridization method, we determined the colocalization pattern of glucocorticoid receptor (GR) and pituitary hormones and the GR messenger RNA (mRNA) expression in the pituitaries of Wistar adult male rats. Immunoreactivity for GR was detected in the nuclei of cells in the anterior and posterior pituitary. Double immunohistochemistry revealed that the colocalization of GR and anterior pituitary hormones occurred in almost 99% of the growth hormone (GH)-producing cells and adrenocorticotropic hormone (ACTH)-producing cells, and in 67% of the thyroid stimulating hormone (TSH)-producing cells. Almost all of the folliculostellate cells (93%), marginal layer cells (94%) in the anterior pituitary, and pituicytes (96%) in the posterior pituitary immunostained for S100 protein antibody were also immunostained with GR. GR mRNA was abundant in the cytoplasm of anterior and intermediate pituitary cells but scattered sparsely in that of the posterior pituitary. These results suggest that glucocorticoids directly influence certain pituitary cells in order to regulate cell function, including the synthesis and/or secretion of hormones.
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PMID:Cellular localization and distribution of glucocorticoid receptor immunoreactivity and the expression of glucocorticoid receptor messenger RNA in rat pituitary gland. A combined double immunohistochemistry study and in situ hybridization histochemical analysis. 993 66

Glucocorticoid production is controlled via the hypothalamo-pituitary-adrenal (HPA) axis by a negative feedback mechanism involving the glucocorticoid receptor (GR). A major site of regulation is the hypothalamus, where the GR is thought to repress the expression of genes such as corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP). To define the role of the GR in this feedback loop in more detail, the content of CRH, AVP and neurophysin in the median eminence of mice carrying a targeted disruption of the GR gene was studied using immunohistochemistry. GR-deficient mice were found to contain five times more CRH in the median eminence than wild-type littermates. In contrast, no significant change in the content of AVP was observed in the outer layer of the median eminence and neurophysin was also only moderately increased. Our studies suggest that, at the hypothalamic level, CRH synthesis is the major target for feedback control by the GR and that transcriptional control of AVP and neurophysin plays only a supportive role in this process.
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PMID:Corticotropin-releasing hormone expression is the major target for glucocorticoid feedback-control at the hypothalamic level. 1008 35

The expression of glucocorticoid receptor (GR) in rat adrenocorticotropin (ACTH)-containing neurons in rat brain was immunohistochemically investigated. ACTH-containing cell bodies were found mainly in the arcuate nucleus. Most of these neurons exhibited GR immunoreactivities in their nuclei. ACTH-containing nerve fibers were distributed in the bed nucleus of the stria terminalis, periventricular nucleus, retrochiasmatic nucleus, parvocellular part of paraventricular nucleus and dorsomedial hypothalamic nucleus. After adrenalectomy there was a marked decrease of ACTH immunoreactivity, as well as GR immunoreactivity, in neurons of the arcuate nucleus, but ACTH immunoreactivity in the fibers was not affected. These results indicate that glucocorticoids up-regulate ACTH and GR production in hypothalamic arcuate neurons, but that glucocorticoid-induced changes could be delayed in the fibers derived from these neurons.
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PMID:Down-regulation of ACTH and glucocorticoid receptor immunoreactivity in hypothalamic arcuate neurons after adrenalectomy in the rat. 1038 Sep 83

Intravenously self-administered cocaine produces a dose-dependent release of adrenocorticotropic hormone (ACTH) and cortisol in male rhesus monkeys. This study investigated whether the acute disruption of cortisol and/or ACTH release had any effect on ongoing cocaine-maintained responding. Four hypothalamic-pituitary-adrenal (HPA) axis inhibitors were examined: etomidate and ketoconazole, both of which are cortisol synthesis inhibitors; astressin, a peptidic corticotropin-releasing factor (CRF) antagonist that binds CRF(1) receptors predominantly in the pituitary gland; and dexamethasone, a highly selective glucocorticoid receptor agonist whose long-lasting effects reduce or abolish the endogenous release of ACTH and cortisol. The reinforcing effects of a range of cocaine doses, with or without pretreatment with an HPA inhibitor, were evaluated using a fixed ratio 30 time-out 10-min schedule of reinforcement in six male monkeys. Blood was sampled before, during, and after self-administration sessions. Self-administration of cocaine increased plasma cortisol and ACTH. Pretreatment with etomidate and ketoconazole dose-dependently inhibited the cocaine-induced rise in cortisol and, at the highest doses, produced a compensatory increase in ACTH release. Astressin and dexamethasone attenuated or abolished cocaine-induced cortisol and ACTH release. Despite the efficacy exhibited by these pretreatments and the variety of mechanisms by which they inhibited the HPA axis, there was no evidence for any change in cocaine-reinforced behavior (response rate or infusion number), an indication that acute changes in the ACTH or cortisol response to cocaine do not play a direct role in modulating cocaine-seeking behavior under these behavioral circumstances.
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PMID:Cocaine-reinforced responding in rhesus monkeys: pharmacological attenuation of the hypothalamic-pituitary-adrenal axis response. 1045 13


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