Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticotropin-releasing factor (CRF) plays a major role in coordinating the endocrine, autonomic, behavioral and immune responses to stress through actions in the brain and the periphery. CRF receptors identified in brain, pituitary and spleen have comparable kinetic and pharmacological characteristics, guanine nucleotide sensitivity and adenylate cyclase-stimulating activity. Differences were observed in the molecular mass of the CRF receptor complex between the brain (58,000 Da) and the pituitary and spleen (75,000 Da), which appeared to be due to differential glycosylation of the receptor proteins. The recently cloned CRF receptor in the pituitary and the brain (designated as CRF1) encodes a 415 amino acid protein comprising seven putative membrane-spanning domains and is structurally related to the calcitonin/vasoactive intestinal peptide/growth hormone-releasing hormone subfamily of G-protein-coupled receptors. A second member of the CRF receptor family encoding a 411 amino acid rat brain protein with approximately 70% homology to CRF1 has recently been identified (designated as CRF2); there exists an additional splice variant of the CRF2 receptor with a different N-terminal domain encoding a protein of 431 amino acids. In autoradiographic studies, CRF receptors were localized in highest densities in the anterior and intermediate lobes of the pituitary gland, olfactory bulb, cerebral cortex, amygdala, cerebellum and the macrophage-enriched zones and red pulp regions of the spleen. CRF can modulate the number of CRF receptors in a reciprocal manner. For example, stress and adrenalectomy increase hypothalamic CRF secretion which, in turn, down-regulates CRF receptors in the anterior pituitary. CRF receptors in the brain and pituitary are also altered as a consequence of the development and aging processes. In addition to a physiological role for CRF in integrating the responses of the brain, endocrine and immune systems to physiological, psychological and immunological stimuli, recent clinical data implicate CRF in the etiology and pathophysiology of various endocrine, psychiatric, neurologic and inflammatory illnesses. Hypersecretion of CRF in the brain may contribute to the symptomatology seen in neuropsychiatric disorders, such as depression, anxiety-related disorders and anorexia nervosa. Furthermore, overproduction of CRF at peripheral inflammatory sites, such as synovial joints may contribute to autoimmune diseases such as rheumatoid arthritis. In contrast, deficits in brain CRF are apparent in neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, as they relate to dysfunction of CRF neurons in the brain areas affected in the particular disorder. Strategies directed at developing CRF-related agents may hold promise for novel therapies for the treatment of these various disorders.
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PMID:Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. 883 89

The effects of CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6 -trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine), a selective corticotropin releasing factor (CRF1) receptor antagonist, were examined in the learned helplessness procedure, a putative model of depression with documented sensitivity to diverse classes of antidepressant drugs. Rats were exposed to a series of inescapable foot shocks on three consecutive days and tested in a shock-escape procedure on the fourth day. Animals exposed to 'helplessness' training performed poorly in the shock-escape test compared with control animals not receiving inescapable shocks. CP-154,526 (10-32 mg/kg, intraperitoneally) dose-dependently reversed the escape deficit when administered 60 min prior to the test session, but had no effect on the performance of control rats not receiving prior exposure to inescapable stress. In comparison, the tricyclic antidepressant imipramine (17.8 mg/kg) reversed the escape deficit after repeated, but not acute, administration. These data support evidence implicating stress systems in the pathophysiology of depression, and suggest potential efficacy of small-molecule CRF receptor antagonists in the treatment of affective disorders.
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PMID:Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. 910 72

The actions of CRF in the brain and in the periphery are mediated through multiple binding sites. There are three receptors, CRF1, CRF2 alpha and CRF2 beta, which encode 411, 415 and 431 amino acid proteins and transduce signals via the stimulation of intracellular cAMP production. The recent identification of high-affinity non-peptide CRF receptor antagonists should allow for rapid progress in drug development of CRF receptor antagonists. In addition to the receptors, the actions of CRF in brain and in the periphery can also be modulated by a binding protein of 322 amino acids. Ligands of CRF-BP, such as CRF (6-33) can elevate brain levels of 'free' CRF and improve learning and memory without stress-like side effects of CRF receptor agonists. Urocortin, a mammalian CRF-related peptide with close sequence homology to fish urotensin, interacts with CRF1, CRF2 receptors and with CRF-BP. These data indicate that CRF receptor antagonists may be useful for the treatment of the disease states where CRF is elevated such as anxiety and depression, anorexia nervosa and stroke and that ligand inhibitors of CRF-BP may be used to elevate brain levels of 'free' urocortin and other CRF-related peptides.
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PMID:Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders. 911 53

Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders, in addition to cardiac and inflammatory disorders. Recently, molecular characterization of CRF1 and CRF2 receptors and the cloning of novel ligands--urocortin, stresscopin-related peptide/urocortin II, and stresscopin/urocortin III--have revealed a far-reaching physiological importance for the family of CRF peptides. Although the physiological roles of the CRF2 receptor remain to be defined, the preclinical and clinical development of specific small-molecule antagonists of the CRF1 receptor opens new avenues for the treatment of psychiatric and neurological disorders.
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PMID:The CRF peptide family and their receptors: yet more partners discovered. 1183 Feb 63

In addition to regulating the neuroendocrine stress response, corticotropin-releasing hormone (CRH) has been implicated in both normal and pathological behavioral and cognitive responses to stress. CRH-expressing cells and their target neurons possessing CRH receptors (CRF1 and CRF2) are distributed throughout the limbic system, but little is known about the regulation of limbic CRH receptor function and expression, including regulation by the peptide itself. Because CRH is released from limbic neuronal terminals during stress, this regulation might play a crucial role in the mechanisms by which stress contributes to human neuropsychiatric conditions such as depression or posttraumatic stress disorder. Therefore, these studies tested the hypothesis that CRH binding to CRF1 influenced the levels and mRNA expression of this receptor in stress-associated limbic regions of immature rat. Binding capacities and mRNA levels of both CRF1 and CRF2 were determined at several time points after central CRH administration. CRH downregulated CRF1 binding in frontal cortex significantly by 4 h. This transient reduction (no longer evident at 8 h) was associated with rapid increase of CRF1 mRNA expression, persisting for >8 h. Enhanced CRF1 expression-with a different time course-occurred also in hippocampal CA3, but not in CA1 or amygdala, CRF2 binding and mRNA levels were not altered by CRH administration. To address the mechanisms by which CRH regulated CRF1, the specific contributions of ligand-receptor interactions and of the CRH-induced neuronal stimulation were examined. Neuronal excitation without occupation of CRF1 induced by kainic acid, resulted in no change of CRF1 binding capacity, and in modest induction of CRF1 mRNA expression. Furthermore, blocking the neuroexcitant effects of CRH (using pentobarbital) abolished the alterations in CRF1 binding and expression. These results indicate that CRF1 regulation involves both occupancy of this receptor by its ligand, as well as "downstream" cellular activation and suggest that stress-induced perturbation of CRH-CRF1 signaling may contribute to abnormal neuronal communication after some stressful situations.
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PMID:Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. 1209 84

Elucidation of the neurobiological basis of depression and other mood disorders is rapidly increasing. Considerable experimental and clinical evidence supports the fundamental roles of serotonin and norepinephrine, as well as the interactions between these systems in the etiology of depression. Substantial evidence has accrued, including changes in neurotransmitter and neurotransmitter metabolite concentrations, reuptake sites, and receptors, to support the hypothesis that alteration in neuronal serotonergic and noradrenergic function occurs in the central nervous system of patients with major depression. Serotonin and norepinephrine represent the major targets of current therapeutic interventions, which may induce longer-term adaptive changes via modulation of the activity of these neurotransmitters. In addition, two neuropeptide neurotransmitters--substance P and corticotropin-releasing factor--have been implicated in the pathophysiology of mood disorders. Preliminary studies have reported the clinical efficacy of a tachykinin NK1 receptor antagonist and a CRF1 receptor antagonist in depressive disorders. Further clarification of the precise neurobiological changes occurring in depression has implications for the use and development of novel effective treatments for this disorder.
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PMID:Recent advances in the neurobiology of depression. 1249 Aug 20

Corticotropin-releasing factor receptor type 1, CRF1, plays a prominent role in the hypothalamic-pituitary-adrenal (HPA) axis and is implicated in the autonomic and behavioral responses to stress. Dysregulation of the CRF system may underlie the pathophysiology of several disorders, including depression and anxiety. The distribution of CRF1 mRNA and CRF1 specific ligand binding has been reported by multiple groups in rodents using in situ hybridization and receptor autoradiography, respectively. More recently, somewhat conflicting rodent anti-CRF1 immunohistochemical studies were reported. In this study we report the generation of an antihuman CRF1 antiserum and provide the first immunohistochemical description of CRF1 distribution in a primate brain, that of the rhesus monkey. The specificity of anti-CRF-R1 antiserum R221 was demonstrated using transfected hCRF1-expressing HEK 293 cells and rhesus monkey pituitary. CRF1-immunoreactive neurons were widespread in the rhesus brain. CRF1 staining was associated with neuronal cell bodies and dendrites and was primarily intracellular, suggesting a high rate of receptor turnover or receptor sequestration. Anti-CRF1 immunoreactivity was most abundant in pituitary, cerebellum, and in portions of brain stem associated with sensorimotor function. CRF1 staining was also observed in cerebral cortex, basal forebrain, portions of the basal ganglia, and thalamus. Staining was relatively low in prefrontal cortex and in limbic areas, which may reflect masking of the N-terminal epitope. The distribution of CRF1 immunoreactivity is suggestive of roles in attentional processing as well as the processing of motor and sensory information.
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PMID:Immunohistochemical visualization of corticotropin-releasing factor type 1 (CRF1) receptors in monkey brain. 1534 73

Corticotropin-releasing factor (CRF) is the major physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a key role in coordinating the mammalian stress response. Substantial data implicates hyperactivity of CRF neuronal systems in the pathophysiology of depression and anxiety disorders. Enhanced CRF expression, release, and function have also been demonstrated during acute withdrawal from several drugs of abuse. Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function. Conversely, measures of urocortin I and CRF2 receptor function were increased. To further scrutinize these findings, we sought to determine whether CRF neuronal systems are activated during spontaneous withdrawal from the triazolobenzodiazepine alprazolam in dependent rats and to characterize the time course, extent, and regional specificity of the patterns of activation. After 14 d of alprazolam administration (90 mg x kg(-1) x d(-1)), spontaneous withdrawal produced activation of the HPA axis, as well as suppression of food intake and weight loss that peaked 24-48 hr after withdrawal. Remarkably, CRF mRNA expression in the cerebral cortex was markedly (>300%) increased over the same time period. Other indices of CRF-CRF1 and urocortin I-CRF2A function, altered by chronic alprazolam treatment as previously described, returned to pretreatment levels over 96 hr. The physiologic significance of this dramatic induction of cortical CRF mRNA expression, as well as whether this occurs during withdrawal from other drugs of abuse is yet to be determined. The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal.
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PMID:Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression. 1549 66

Hypothalamic CRF plays a central role in the coordination of endocrine and behavioral responses to stress and it is also involved in the pathophysiology of several neuropsychiatric diseases including depression, anxiety and addiction. In the mammals, the CRF family of peptides includes CRF, urocortin (Ucn), Ucn I, and Ucn II while was enriched with new members, the urocortins. Their biological effects are mediated by the CRF1 and CRF2 receptors, which belong to the G-protein-coupled receptor super family. Multiple research groups have demonstrated during the last decade the expression of the CRF peptides and their receptors in several components of the immune system and their participation in the ad hoc regulation of inflammatory phenomena. Non-peptide CRF1 antagonists have been recently synthesized for the treatment of CNS related diseases, such as anxiety, depression and drug abuse. In the gastrointestinal tract, these compounds open new therapeutic options in the treatment of lower-GI inflammatory diseases associated to CRF, such as the chronic inflammatory bowel syndromes, irritable bowel disease and ulcerative colitis while Ucn, Ucn I, Ucn II or synthetic non-peptide CRF2 agonists may be useful in the treatment of upper-GI inflammatory diseases. In human endometrium, CRF1 antagonists may be used as abortive agents interfering with the inflammatory phenomena taking place during the implantation of the conceptus. They thus may represent a new class of nonsteroidal inhibitors of implantation. These two examples illustrate the potential therapeutic significance of the CRH in regulating inflammatory phenomena in an ad hoc approach without affecting the rest of the immune system.
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PMID:The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. 1597 83

The identification of the various elements of the Corticotropin Releasing Factor (CRF) system including the characterisation of four mammalian CRF-related peptides, the cloning of two CRF receptor subtypes 1 and 2 (CRF1; CRF2) and the development of selective CRF1 receptor antagonists has allowed investigators to establish an important role for the CRF signalling pathways in coordinating the physiological and behavioural components of the stress response. In particular, compelling preclinical evidence showed that both central and peripheral injection of CRF mimicked stress-induced stimulation of colonic motility, transit, defaecation, and occurrence of diarrhoea along with degranulation of mast cells, and increased secretion of prostaglandin E2, mucus, and ionic permeability. Central CRF also increased abdominal pain from colorectal distention in rats and peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. Non-selective CRF antagonists for receptors 1 and 2 and selective CRF, antagonists inhibit exogenous (central or peripheral) CRF, and acute stress-induced stimulation of colonic motor and secretory function and visceral hyperalgesia. CRF1 receptors mediate stress-related anxiogenic and depression-like behaviours in rodents and CRF, antagonist reduced depression in a phase II clinical trial. These findings lend support to the hypothesis that hyperactivation of CRF1 receptors may contribute to the co-morbidity of anxiety and depression and irritable bowel syndrome. Targeting these pathways with selective CRF1 antagonists may be a novel therapeutic venue for diarrhoea-predominant IBS patients.
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PMID:Role of corticotropin releasing factor receptor subtype 1 in stress-related functional colonic alterations: implications in irritable bowel syndrome. 1614 97


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