Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothalamic-pituitary-adrenal (HPA) axis plays important roles in maintaining alertness and modulating sleep. Dysfunction of this axis at any level (CRH receptor, glucocorticoid receptor, or mineralocorticoid receptor) can disrupt sleep. Herein, we review normal sleep, normal HPA axis physiology and circadian rhythm, the effects of the HPA axis on sleep, as well as the effects of sleep on the HPA axis. We also discuss the potential role of CRH in circadian-dependent alerting, aside from its role in the stress response. Two clinically relevant sleep disorders with likely HPA axis dysfunction, insomnia and obstructive sleep apnea, are discussed. In insomnia, we discuss how HPA axis hyperactivity may be partially causal to the clinical syndrome. In obstructive sleep apnea, we discuss how HPA axis hyperactivity may be a consequence of the disorder and contribute to secondary pathology such as insulin resistance, hypertension, depression, and insomnia. Mechanisms by which cortisol can affect slow wave sleep are discussed, as is the role the HPA axis plays in secondary effects of primary sleep disorders.
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PMID:On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. 1572 14

Koso-san (Xiang-Su-San in Chinese), a Kampo (Japanese herbal) medicine, is used clinically in East Asia for the treatment of depression-like symptoms associated with the initial stage of the common cold, allergic urticaria due to food ingestion, irritable bowel syndrome, chronic fatigue syndrome, insomnia, and autonomic imbalance. However, the antidepressant-like activity of Koso-san has never been evaluated scientifically. In this study, ddY mice subjected to a combination of forced swimming and chronic mild stresses were termed depression-like model mice. The degree of the depression-like state was measured by the animal's duration of immobility using the forced swimming test (FST). Oral administration of Koso-san (1.0 g/kg/body wt./day, 9 days) significantly shortened the duration of immobility of the depression-like model mice in the FST; however, locomotor activity was not affected. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the pathophysiology of depression. Levels of corticotropin-releasing hormone mRNA expression in the hypothalamus and proopiomelanocortin mRNA expression in the pituitary were significantly increased, and glucocorticoid receptor protein expression in the hypothalamus paraventricular nucleus was downregulated in the depression-like model mice. However, Koso-san ameliorated these alterations to the normal conditions. The results of this study suggest that Koso-san shows the antidepressant-like effect through suppressing the hyperactivity of the HPA axis in depression-like model mice.
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PMID:Antidepressant-like activity of a Kampo (Japanese herbal) medicine, Koso-san (Xiang-Su-San), and its mode of action via the hypothalamic-pituitary-adrenal axis. 1651 52

Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. These hormones influence a large percentage of the expressed human genome and their effects spare almost no organs or tissues. Glucocorticoids influence many functions of the central nervous system, such as arousal, cognition, mood and sleep, the activity and direction of intermediary metabolism, the maintenance of a normal cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, as well as growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems. The presence of multiple GR monomers and dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic. Based on ample evidence, we present our conception that glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common psychiatric and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid component.
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PMID:Glucocorticoid action networks and complex psychiatric and/or somatic disorders. 1751 90

Depression is one of the leading causes of morbidity worldwide and represents a huge burden to society. As with many other psychiatric disorders, a genetic basis for depression has been identified. Evidence for the role of circadian genes in depression is particularly compelling. Circadian gene mutations are also associated with circadian rhythm disorders such as familial advanced sleep phase syndrome, delayed sleep phase syndrome, and non-24-hour sleep-wake syndrome. Such disorders, plus the other manifestations of a disrupted circadian system such as hormone dysregulation, are often observed among those with depression. This suggests a shared aetiology between circadian disruption and depression, although the exact mechanisms underlying the association are unclear. This paper reviews the molecular mechanisms involved in depression, with an emphasis on circadian genes. Twin studies in depression have reported probandwise concordance rates of 40% and 70% using narrow and broad diagnostic criteria, respectively, and heritability of over 85% for bipolar disorder. In association studies, increased susceptibility to depression has been noted in those with polymorphisms in the following: D-amino-acid-oxidase activator/G30 gene complex, glucocorticoid receptor gene, serotonin transporter gene, tryptophan hydroxylase 2 gene, dopamine transporter gene and G protein-coupled receptor 50 gene. Polymorphisms in these genes have also been linked to a better or worse response to antidepressant therapy, an increased likelihood of responding poorly to adversity and increased suicide ideation. Polymorphisms in the CLOCK, BMAL1, Per3 and TIMELESS genes have been associated with susceptibility to mood disorder, and single nucleotide polymorphisms and haplotypes in several circadian genes have been observed among those displaying certain circadian phenotypes, including worse mood in the evening, insomnia in mania and early, middle or late insomnia in depression. Manipulation of the circadian timing system via sleep deprivation, bright light or pharmacological therapy has also been shown to alleviate depressive symptoms, providing further evidence for the role of circadian dysfunction in depression pathophysiology. The new antidepressant agomelatine is the first melatonergic antidepressant with an innovative mode of action: it is a melatonergic MT(1), MT(2) receptor agonist and 5-HT(2c) antagonist, and is able to restore the internal clock, which is profoundly disturbed in depression, thus being efficacious in major depressive disorders. In conclusion, a wealth of evidence is now available supporting a genetic basis for depression. The apparent importance of mutations in the circadian genes in determining disease susceptibility, disease recurrence and response to treatment suggests that the circadian pathway represents an attractive target for pharmacological manipulation to improve management of this debilitating disorder.
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PMID:Disruption of the circadian timing systems: molecular mechanisms in mood disorders. 1970 22

Glucocorticoids contribute to the maintenance of basal and stress-related homeostasis in all higher organisms, and influence a large proportion of the expressed human genome, and their effects spare almost no organs or tissues. Glucocorticoids regulate many functions of the central nervous system, such as arousal, cognition, mood, sleep, the activity and direction of intermediary metabolism, the maintenance of a proper cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, and growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems, including large and small G proteins. The presence of multiple GR monomers and homo- or hetero-dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggest that the glucocorticoid signaling system is highly stochastic. Glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common behavioral and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid-regulated component.
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PMID:Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. 1990 38