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)

Regulation of serotonin (5-HT)1A receptor expression in brain is implicated in mood disorders such as depression and anxiety. Transcriptional activity of the human 5-HT1A receptor gene was strongly repressed by a negative regulatory region containing a consensus repressor element-1 (RE-1) and two copies of the dual repressor element (DRE) identified in the rat 5-HT1A receptor gene. REST/NRSF, a silencer of neuronal genes, bound the 5-HT1A RE-1 and repressed the 5-HT1A promoter. Inactivation of RE-1 completely abolished REST-mediated repression, but resulted in only partial (15-50%) de-repression of basal 5-HT1A promoter activity. The human 5-HT1A DRE sequences bound specifically to the novel repressor Freud-1 (5'repressor element under dual repression binding protein-1) and conferred repressor activity at 5-HT1A or SV40 promoters. In 5-HT1A-negative cells [L6, human embryonic kidney (HEK) 293], the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) abolished repression mediated by both RE-1/REST and DRE/Freud-1, and induced almost complete de-repression of the 5-HT1A gene. By contrast, in 5-HT1A-expressing neuronal cells (RN46A, SN-48) TSA blocked RE-1/REST repression, but did not affect DRE/Freud-1-mediated repression. Thus in contrast to REST, Freud-1 mediates HDAC-independent repression of the 5-HT1A receptor promoter in neuronal 5-HT1A-positive cells, suggesting that HDAC recruitment might influence neuron-specific gene expression by further silencing expression in non-neuronal tissue.
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PMID:Cell type-dependent recruitment of trichostatin A-sensitive repression of the human 5-HT1A receptor gene. 1475 6

The serotonin system is implicated in major depression and suicide and is negatively regulated by somatodendritic 5-HT1A autoreceptors. Desensitization of 5-HT1A autoreceptors is implicated in the 2- to 3-week latency for antidepressant treatments. Alterations in 5-HT1A receptor levels are reported in depression and suicide, and gene knockout of the 5-HT1A receptor results in an anxiety phenotype, suggesting that abnormal transcriptional regulation of this receptor gene may underlie these disorders. The 5-HT1A receptor gene is negatively regulated in neurons by repressors including REST/NRSF, Freud-1, NUDR/Deaf-1, and Hes5. The association with major depression, suicide, and panic disorder of a new functional 5-HT1A polymorphism at C(-1019)G that selectively blocks repression of the 5-HT1A autoreceptor by NUDR further suggests a causative role for altered regulation of this receptor in predisposition to mental illness. The authors review evidence that altered transcription of the 5-HT1A receptor can affect the serotonin system and limbic and cortical areas, leading to predisposition to depression.
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PMID:5-HT1A receptors, gene repression, and depression: guilt by association. 1553 42

Restless legs syndrome (RLS) is a neurological disorder characterized by a compelling urge to move, accompanied by disturbing sensations within the legs. It is now recognized that RLS is a common condition that has a substantial impact on sleep, daily activities and quality of life. Recent data from the REST (RLS Epidemiology, Symptoms, and Treatment) general population study show that symptoms of RLS are present in approximately 7% of the general population, and that 2-3% experience moderate or severe symptoms at least twice a week. Amongst this RLS cohort, approximately 88% reported sensory disturbances and 76% reported sleep-related symptoms. These symptoms had a marked effect on everyday life, with up to 50% of the RLS cohort reporting disruption of everyday activities or personal relationships. Sleep disturbances in turn lead to impaired daytime functioning. RLS is associated with a significant impairment of quality of life, comparable with that seen in chronic medical conditions such as diabetes or depression. Given the significant burden of morbidity associated with RLS, there is a strong case for treatment in patients with troublesome symptoms.
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PMID:Time to REST: epidemiology and burden. 1693 Mar 78

Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.
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PMID:[Neural network abnormalities caused by alcohol: approach for repair using neural stem cells]. 1851 85

Recent clinical neuroimaging studies have suggested the morphological brain changes occur and progress in the course of alcoholism and depression. The abnormality of neurogenesis has emerged as a potential epidemiological mechanism of these diseases. Previously, we have indicated the low dose of ethanol that could not influence on the survival of neurons and neural stem cell (NSC) suppress differentiation to neurons but glias through activation of neuron-restrictive silencing factor/repressor element-1 silencing transcription factor (NRSF/REST). We revealed the endoplasmic reticulum function and trophic factor signaling change implicated in this mechanism of ethanol action on NSC differentiation change. The analysis of potentials of psychotropic drugs on the ethanol-induced NSC function change may reveal the possible biological way of neural network impairment and its repair. Furthermore, the approach of using stem cells such as intravenous NSC transplantation can be a useful method to clarify the neural network reconstruction damaged by ethanol. The importance of interactive analysis of in vitro to in vivo should be documented for the pathophysiological understanding and new therapy development against alcohol-induced brain damage.
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PMID:[The analysis of impairment and repair of neural network by ethanol: in vitro and in vivo studies using neurons and neural stem cells]. 1923 Apr 85

Huntington's disease (HD) is an incurable, fatal neurodegenerative disorder that is caused by a polyglutamine expansion in the huntingtin (Htt) protein. Neuronal death in the striatum-the most obvious manifestation of the disease-is likely to result from widespread dysregulation of gene expression in various brain regions. To date, several potential mechanisms for this have been discovered, including one involving REST (RE1-Silencing Transcription Factor), a master regulator of neuronal genes. Recently, independent studies have demonstrated that post-transcriptional gene regulation by microRNAs is also disrupted in HD. Expression of key neuronal microRNAs-including mir-9/9*, mir-124 and mir-132-is repressed in the brains of human HD patients and mouse models. These changes occur downstream of REST, and are likely to result in major disruption of mRNA regulation and neuronal function. In this study we will discuss these findings and their implications for our understanding of HD. Using updated bioinformatic analysis, we predict 21 new candidate microRNAs in HD. We propose future strategies for unifying large-scale transcriptional and microRNA datasets with the aim of explaining HD aetiology. By way of example, we show how available genomic datasets can be integrated to provide independent, analytical validation for dysregulation of REST and microRNA mir-124 in HD. As a consequence, gene ontology analysis indicates that HD is characterised by a broad-based depression of neural genes in the caudate and motor cortex. Thus, we propose that a combination of REST, microRNAs and possibly other non-coding RNAs profoundly affect the neuronal transcriptome in HD.
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PMID:Gene dysregulation in Huntington's disease: REST, microRNAs and beyond. 1945 43

Alcohol is a well-known cytotoxic agent which causes various kinds of neuronal damage. In spite of thousands of published studies, the true mechanism of alcohol-induced neuronal damage remains unclear. Neurogenesis is the generation of neurons from neural stem cells (NSCs) and occurs in predominantly two regions of the brain, the subventricular zone and the dentate gyrus of the hippocampus. NSCs are the self-renewing, multipotent precursor cells of neurons, astrocytes, and oligodendrocytes in the central nervous system. Recent studies have begun to illuminate the role of neurogenesis in the biological and cellular basis of psychiatric disorders and several clinical symptoms seen in alcoholism such as depression, cognitive impairment, underlying stress and brain atrophy have been linked to impaired neurogenesis. Heavy alcohol consumption decreases neurogenesis in animals, while in vitro studies have shown decreased generation of new neurons after alcohol exposure. These findings suggest that decreased neurogenesis is important in the pathophysiology of alcoholism. Neurogenesis can be divided into four stages; proliferation, migration, differentiation and survival. Our in vitro studies on NSCs showed that alcohol decreased neuronal differentiation at doses lower than those that affected cell survival and suggested that neuron-restrictive silencer factor, or repressor element-1 silencing transcription factor (NRSF/REST) could be involved in alcohol-induced inhibition of neuronal differentiation. In an animal model of fetal alcohol effects behavioral symptoms improved after NSC transplantation. Neurogenesis could be the target for new strategies to treat alcohol related disorders.
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PMID:Biological studies on alcohol-induced neuronal damage. 2004 4

Recent biological studies suggest the existence of the common pathophysiological aspects in alcoholism and depression. Postmortem studies have revealed the impairment of cAMP signaling in the patients with alcoholism. The similar alteration of cAMP signaling was also reported in postmortem brains of depressed patients. In this study, we supported the notion that neurogenesis would be essential in pathophysiology of both alcoholism and depression. Alcohol affected the function of neural stem cells (NSCs) and decreased neurogenesis at doses which did not affects cell survival, and treatment of antidepressant or moodstabilizer rescued the alcohol-induced suppression of neurogenesis. As the key mechanism of NSC differentiation change by ethanol and psychotropics, we focused on the transcriptional repressor, NRSF/REST activity change. Our in vitro studies demonstrated the NRSF/REST activation by ethanol and suppressive effect of antidepressants and lithium against its activation by ethanol. We further described the ERK reduction and ER stress in the cellular mechanism of NRSF/REST activation. All these findings suggested that cAMP-CREB cascade reduction and NRSF/REST activation may be common underlying mechanisms in the pathophysiology of alcoholism and depression.
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PMID:The common aspects of pathophysiolgy of alcoholism and depression. 2007 63

There is growing evidence suggesting that early life events have long-term effects on the neuroendocrine and behavioral developments of rodents. However, little is known about the involvement of early life events in the susceptibility to subsequent stress exposure during adulthood. The present study characterized the effect of maternal separation, an animal model of early life adversity, on the behavioral response to repeated restraint stress in adult rats and investigated the molecular mechanism underlying behavioral vulnerability to chronic stress induced by the maternal separation. Rat pups were separated from the dams for 180 min per day from postnatal day 2 through 14 (HMS180 rats). We found that, as young adults, HMS180 rats showed a greater hypothalamic-pituitary-adrenal axis response to acute restraint stress than nonseparated control rats. In addition, repeatedly restrained HMS180 rats showed increased depression-like behavior and an anhedonic response compared with nonrestrained HMS180 rats. Furthermore, HMS180 rats showed increased expression of REST4, a neuron-specific splicing variant of the transcriptional repressor REST (repressor element-1 silencing transcription factor), and a variety of REST target gene mRNAs and microRNAs in the medial prefrontal cortex (mPFC). Finally, REST4 overexpression in the mPFC of neonatal mice via polyethyleneimine-mediated gene transfer enhanced the expression of its target genes as well as behavioral vulnerability to repeated restraint stress. In contrast, REST4 overexpression in the mPFC of adult mice did not affect depression-like behaviors after repeated stress exposure. These results suggest that the activation of REST4-mediated gene regulation in the mPFC during postnatal development is involved in stress vulnerability.
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PMID:Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents. 2106 6

Previous studies have shown that intermittent cold stress (ICS) induces depression-like behaviors in mammals. Tupaia belangeri (the tree shrew) is the only experimental animal other than the chimpanzee that has been shown to be susceptible to infection by hepatitis B and C viruses. Moreover, full genome sequence analysis has revealed strong homology between host proteins in Tupaia and in humans and other primates. Tupaia neuromodulator receptor proteins are also known to have a high degree of homology with their corresponding primate proteins. Based on these similarities, we hypothesized that induction of ICS in Tupaia would provide a useful animal model of stress responses. We exposed young adult Tupaia to ICS and observed decreases in body temperature and body weight in both female and male Tupaia, suggesting that Tupaia are an appropriate animal model for ICS studies. We further examined the efficacy of a new small-molecule compound, C737, against the effects of ICS. C737 mimics the helical structure of neuron-restrictive silencer factor (NRSF/REST), which regulates a wide range of target genes involved in neuronal function and pain modulation. Treatment with C737 significantly reduced stress-induced weight loss in female Tupaia; these effects were stronger than those elicited by the antidepressant agomelatine. These results suggest that Tupaia represents a useful non-rodent ICS model. Our data also provide new insights into the function of NRSF/REST in stress-induced depression and other disorders with epigenetic influences or those with high prevalence in women.
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PMID:Establishment of an intermittent cold stress model using Tupaia belangeri and evaluation of compound C737 targeting neuron-restrictive silencer factor. 2704 57


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