Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression.
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PMID:Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. 167 67

By means of double immunolabeling procedures it has been possible to demonstrate glucocorticoid receptor (GR) immunoreactivity (IR) in large numbers of various peptidergic neurons of the brain including neurons containing gastrointestinal peptides, opioid peptides, and peptides with a hypothalamic hormone function. For each peptide system, however, marked heterogeneities exist among brain regions. Thus, in the neocortex and the hippocampal formation most of the brain peptide neurons lack GR IR, while the same types of peptide neurons in the arcuate and paraventricular nucleus [e.g. neuropeptide Y (NPY), somatostatin (SRIF) and the cholecystokinin (CCK) neurons] possess strong GR IR. Furthermore, in the arcuate, parvocellular part of the paraventricular nuclei and the central amygdaloid nucleus practically all the peptidergic neurons are strongly GR IR, while in the lateral hypothalamus, mainly the neurotensin (NT) and galanin (GAL) IR neurons are GR IR. These marked differences among areas probably reflect functional differences dependent upon their participation in stress regulated circuits. All the paraventricular NT, corticotropin-releasing factor (CRF), growth hormone-releasing factor (GRF), thyrotropin-releasing hormone (TRH) and SRIF IR neurons appear to contain GR IR, while the luteinizing hormone-releasing hormone (LHRH) IR neurons lack GR IR, underlying the importance of glucocorticoids (GC) in controlling endocrine function. Finally, the GC may influence pain and mood control mainly via effects on enkephalin (ENK) neurons especially in the basal ganglia (mood) and on all beta-endorphin (beta-END) neurons of the arcuate nucleus, while most of the dynorphin neurons are not directly controlled by GC.
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PMID:Central peptidergic neurons as targets for glucocorticoid action. Evidence for the presence of glucocorticoid receptor immunoreactivity in various types of classes of peptidergic neurons. 168 65

Aging affects the hypothalamus-pituitary-adrenocortical (HPA) system in various ways. It affects the receptors for glucocorticosteroids in the limbic system, the hypothalamus and the pituitary; the basal and stress-induced secretion of proopiomelanocortin-derived peptides and glucocorticoids; and the neuronal integrity, especially in the hippocampus. The homeostatic actions of glucocorticoids occur through the glucocorticoid and the mineralocorticoid receptors. It has been hypothesized that the balance between these two receptors, which are co-localized in the hippocampus, determines the basal HPA activity and the magnitude of the response to challenges. Feedback actions of glucocorticoids are mediated via glucocorticoid receptors in the hypothalamus and the pituitary. In aged rats many changes in the binding capacity of the mineralocorticoid receptor and glucocorticoid receptor and in the regulation of the HPA activity have been reported, but the findings often seem contradictory. The only consistent finding has been that the binding capacity of mineralocorticoid receptor in the hippocampus is reduced. The number of glucocorticoid receptors may be increased, reduced or unchanged in senescent rats. In old dogs the receptor changes were largely confined to mineralocorticoid receptor, there being a 60% reduction in the binding capacity in the limbic system, but glucocorticoid receptor was unchanged in all brain regions. Senescent dogs also had an increased basal secretion of ACTH, and of cortisol. The old dogs had exaggerated responses to stress and to administered corticotropin-releasing hormone, but the termination of the response by the feedback mechanism was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aging and the hypothalamus-pituitary-adrenocortical axis, with special reference to the dog. 180 5

This paper examines the treatment of obesity, using a feedback model of nutrient regulation. A feedback model contains afferent signals and a central controller that transduces afferent information into efferent signals that modulate the controlled system. Using this model and the receptor hypothesis for drug action, a variety of current and potential therapeutic approaches are discussed. Among the more promising approaches would be cholecystokinin agonists, small molecules that mimic ketoacids, agonists to corticotropin-releasing hormone, beta-3 agonists, antagonists to opioid peptides, antagonists to neuropeptide Y, glucocorticoid receptor antagonists, and growth hormone agonists. Since a number of mechanisms can influence body fat and nutrient partitioning, it is likely that optimal therapy will involve use of more than one pharmacologic agent.
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PMID:Treatment for obesity: a nutrient balance/nutrient partition approach. 201 19

A number of changes in anterior pituitary corticotrophs occur after chronic footshock. These include increased ACTH and beta-endorphin content and a loss of glucocorticoid negative feedback on corticotropin-releasing hormone (CRH)-stimulated ACTH and beta-endorphin secretion, without changes in sensitivity to ovine CRH examined in vitro. The present studies were undertaken to determine whether the in vitro changes were reflected by similar changes in vivo. We developed a fast feedback paradigm using a 5-min swim stress as challenge, with injection of saline or corticosterone immediately prior to swim. Corticosterone reliably decreased ACTH and beta-endorphin responses to swim over the 30-min period studied. This feedback inhibition did not occur in rats that were either exposed to 30 min of chronic footshock for 7 or 14 days or in rats that were treated with corticosterone daily for 14 days in a regimen that has been reported to decrease hippocampal glucocorticoid receptors. By contrast, in rats exposed to the less intense stimulus of 30 min swim for 14 days, the fast feedback action of corticosterone was intact. These results suggest that both fast and delayed feedback corticosterone-inhibitory mechanisms may be blocked by relatively high levels of chronic stress or by chronic treatment with corticosterone, possibly as a consequence of decreased hippocampal glucocorticoid receptor number.
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PMID:Decreased sensitivity to glucocorticoid fast feedback in chronically stressed rats. 216 11

Glucocorticoids regulate gene expression by causing the glucocorticoid receptor to bind to an enhancer-like DNA element termed the glucocorticoid regulatory element (GRE). The resultant effect on transcription of specific genes causes a cascade of intracellular events that determines the growth or differentiated function of the target tissue. Although virtually all animal tissues respond to glucocorticoids, it has proven difficult to elucidate the molecular events which underlie physiologically important glucocorticoid effects such as lymphocyte death or poor wound healing. In this paper, a tryptic fragment of the glucocorticoid receptor (17K-GR) is shown to bind selectively to DNA containing a GRE. When a mixture of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) region and plasmid vector DNA was extracted using the intact glucocorticoid receptor or the 17K-GR, the 17K-GR retained a greater proportion of LTR vs. plasmid DNA. The 17K-GR-LTR complex was also more resistant to salt extraction. Extraction of Bam HI-digested mouse genomic DNA resulted in enrichment of the pro-opiomelanocortin (POMC) gene 5' fragment (which contains a GRE) vs. the 3' fragment which does not. A mouse genomic phage library was enriched for GRE-containing sequences by extraction using the 17K-GR. The frequency of POMC-positive plaques was determined to gauge enrichment of down-regulated genes, and the frequency of phosphoenolpyruvate carboxy-kinase-positive plaques was determined to gauge enrichment of up-regulated genes. The frequencies obtained (1.2 x 10(-3) and 3.5 x 10(-3), respectively) indicated that a family of glucocorticoid-regulated genes totaling approximately 300 had been isolated in a genomic sublibrary.
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PMID:Isolation of a genomic sublibrary enriched for glucocorticoid-regulated genes. 234 94

Inbred Lewis (LEW/N) female rats develop an arthritis in response to group A streptococcal cell wall peptidoglycan polysaccharide (SCW), which mimics human rheumatoid arthritis. Histocompatible Fischer (F344/N) rats do not develop arthritis in response to the same SCW stimulus. To evaluate this difference in inflammatory reactivity, we examined the function of the hypothalamic-pituitary-adrenal (HPA) axis and its ability to modulate the development of the inflammatory response in LEW/N and F344/N rats. We have found that, in contrast to F344/N rats, LEW/N rats had markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, and synthetic rat/human corticotropin-releasing hormone. LEW/N rats also had smaller adrenal glands and larger thymuses. Replacement doses of dexamethasone decreased the severity of LEW/N rats' SCW-induced arthritis. Conversely, treatment of F344/N rats with the glucocorticoid receptor antagonist RU 486 or the serotonin antagonist LY53857 was associated with development of severe inflammatory disease, including arthritis, in response to SCW. These findings support the concept that susceptibility of LEW/N rats to SCW arthritis is related to defective HPA axis responsiveness to inflammatory and other stress mediators and that resistance of F344/N rats to SCW arthritis is regulated by an intact HPA axis-immune system feedback loop.
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PMID:Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. 253 40

Since the discovery of CRH in 1981, several investigators have reported abnormalities of the hypothalamic-pituitary-adrenal (HPA) system in response to direct stimulation of the corticotroph cells in patients with psychiatric disorders. To further explore HPA system integrity in major depressive disorders, 13 drug-free patients and normal subjects matched for age, sex, ovarian status, and body weight received 100 micrograms synthetic human CRH as an iv bolus dose. Compared to that in the normal subjects, in the depressed patients a significant attenuation of the net ACTH release after CRH administration (772 +/- 597 vs. 263 +/- 286 pmol/min.L; P less than 0.02) was observed, while beta-endorphin and cortisol responses did not differ significantly between the groups. The magnitudes of ACTH and cortisol release were negatively correlated in the patient group only (r = -0.67; P less than 0.01). Thus, the blunted ACTH response to CRH in depression might be related to hypercortisolemia, while the implications of the apparent dissociation of ACTH and beta-endorphin after CRH administration still remain unclear. Our data support the hypothesis that the hyperactivity of the HPA system in depression most likely is a consequence of CRH hypersecretion, the origin of which may be explained by abnormal central glucocorticoid receptor or neurotransmitter regulation.
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PMID:Blunted adrenocorticotropin but normal beta-endorphin release after human corticotropin-releasing hormone administration in depression. 254 28

Specific DNA sequence elements which contain binding sites for the glucocorticoid receptor mediate the action of glucocorticoid hormones on gene transcription. In glucocorticoid-inducible genes, these glucocorticoid-responsive elements behave as hormone-inducible enhancers of transcription. We have taken advantage of the bovine papillomavirus (BPV) system to test the stringency of glucocorticoid regulation of transcription. BPV episomes were constructed to contain two hormone-regulated transcription units in close proximity; one transcription unit is under control of a glucocorticoid-inducible promoter (mouse mammary tumor virus) while the other is under control of a glucocorticoid-inhibited promoter (pro-opiomelanocortin). Glucocorticoids independently regulated transcription of the two physically linked transcription units, irrespective of their relative orientation and of their proximity on the BPV episomes. This result contrasts with the so-called position-independent activity of enhancers and suggests that the multicomponent organization of eucaryotic promoters restricts the action of hormone-responsive regulatory elements to a specific transcription unit, thus accounting for the stringency of hormonal regulation observed in vivo.
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PMID:Independent glucocorticoid induction and repression of two contiguous responsive genes. 255 Jul 96

Monoclonal antibody (MAb49) against the rat liver glucocorticoid receptor was used to evaluate glucocorticoid receptor (GR) immunoreactive structures in the brain of the japanese quail, Coturnix coturnix japonica. Using the avidin-biotin technique, the immunoreaction was present in the nerve cell nuclei in intact male birds. High density of glucocorticoid receptor-like immunoreactivity was found in the tubero-infundibular area, nucleus paraventricularis, posteromedialis and lateralis hypothalami, lateral septum and in some brainstem nuclei. Cerebellar cortex was also immunopositive. In contrast to mammals, no immunoreactive cell nuclei were found in the hippocampal region. The glucocorticoid receptors were colocalized with adrenocorticotropin (ACTH) immunoreactivity in the tubero-infundibular region, while corticotropin releasing factor (CRF) positive cells in the paraventricular nucleus did not contain glucocorticoid receptor-like immunoreactivity in their cell nuclei.
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PMID:Distribution of glucocorticoid receptor-like immunoreactivity in the brain, and its relation to CRF and ACTH immunoreactivity in the hypothalamus of the japanese quail, Coturnix coturnix japonica. 255 33


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