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

The expression of the nuclear c-JUN, JUN B, JUN D, c-FOS, FOS B, KROX-24, and CREB transcription factors was investigated in the cortex of adult rats by immunocytochemistry. The expression patterns were studied in untreated rats and up to 24 hours following topical application of 1 M KCl to the cortical surface (KCl) or i.v. injection of bicuculline (BIC). Topical KCl induced cortical spreading depression and systemic injection of bicuculline evoked generalized tonic-clonic seizures. In untreated rats, JUN B, c-FOS, and FOS B were expressed in a small number of neurons in the piriform, perirhinal, entorhinal, and insular cortex and in layers II, III, and VI of all neocortical areas. In contrast, c-JUN, JUN D, and KROX-24 were expressed in all cortical layers but with different intensities of immunoreactivity (IR): c-JUN-IR was generally weak and predominantly present in layers II, III, and VI. JUN D-IR was equally strong in all layers. KROX-24 showed a prominent expression in layers II, IV, and VI. The CREB protein exhibited a slight preponderance in layer II and piriform cortex. Following KCl or BIC, a strong induction was seen for c-FOS, JUN B, and KROX-24, whereas c-JUN, JUN D, and FOS B showed only a moderate increase compared to basal levels. Changes of CREB-IR could not be detected. The localization of induced JUN, FOS, and KROX proteins reflected the pattern of labelling in untreated animals but demonstrated a higher intensity of labelling and an increased number of immunoreactive nuclei. The intensity and persistence of IR as well as the number of labelled cells following BIC exceeded those following KCl. Following BIC, increased levels of FOS B and JUN D were still present after 24 hours. Counterstaining with cresyl-violet and GFAP, a marker for astrocytes, revealed that JUN, FOS, and KROX proteins were expressed in neurons but not in glial cell populations. The present data demonstrate that CREB, JUN, FOS, and KROX transcription factors exhibit a layer-specific expression in the cerebral cortex with only slight area-specific differences both in untreated rats and following stimulation with KCl and BIC. The expression of transcription factor proteins indicate complex molecular genetic changes in cortical neurons due to pathophysiological events such as seizure activity and spreading depression.
 ...
PMID:JUN, FOS, KROX, and CREB transcription factor proteins in the rat cortex: basal expression and induction by spreading depression and epileptic seizures. 834 7

The influence of serotonin (5-HT) on neuronal function is mediated by regulation of receptor-coupled intracellular signal transduction pathways, and the therapeutic action of 5-HT selective reuptake inhibitors (SSRIs), as well as other types of antidepressants, most likely involves regulation of these intracellular pathways. The cyclic adenosine monophosphate (cAMP) second messenger system is one pathway that could be involved in antidepressant action. Chronic administration of antidepressants, including SSRIs, up-regulates the cAMP pathway at several levels, including increased expression of the cAMP response element binding protein (CREB). Among the multiple target genes that could be regulated by CREB and that could be involved in antidepressant actions and the pathophysiology of depression in brain-derived neurotrophic factor (BDNF). Stress decreases the expression of BDNF, and reduce levels of this neurotrophic factor could contribute to the atrophy and decreased function of stress-vulnerable hippocampal neurons. In contrast, antidepressant treatment increases the expression of BDNF in hippocampus, and could thereby reverse the stress-induced atrophy of neurons or protect these neurons from further damage. Up-regulation of the cAMP and BDNF systems has resulted in a novel model for the mechanism of action of antidepressants and new targets for the development of therapeutic agents.
 ...
PMID:Novel therapeutic approaches beyond the serotonin receptor. 975 54

Various effects of antidepressant drugs on gene transcription have been described and altered gene expression has been proposed as being a common biological basis underlying depressive illness. One target for the common action of antidepressants is a modifying effect on the regulation of postreceptor pathways and genes related to the cAMP cascade. Recent studies have demonstrated that long-term antidepressant treatment resulted in sustained activation of the cyclic adenosine 3',5'-monophosphate system and in increased expression of the transcription factor cAMP response element binding protein (CREB). A transgenic animal model of depression with impaired glucocorticoid receptor function was used to investigate the effect of chronic antidepressant treatments on CREB expression in different brain areas. Wild-type and transgenic mice received one administration of saline, desipramine, or fluoxetine, daily for 21 days. The effects of antidepressants on CREB mRNA were analyzed using a sensitive RNase protection assay. Antidepressant treatment resulted in a neuroanatomically and animal specific expression pattern of CREB. Our findings suggest that life-long central glucocorticoid receptor dysfunction results in an altered sensitivity with respect to the effects of antidepressants on the expression of CREB.
 ...
PMID:Altered regulation of CREB by chronic antidepressant administration in the brain of transgenic mice with impaired glucocorticoid receptor function. 1192 85

Recent studies demonstrate that the molecular elements known to regulate neuronal plasticity in models of learning and memory are also involved in the actions of drugs used for the treatment of depression and bipolar disorder. This includes up-regulation of transcription factors, such as the cAMP response element binding protein and neurotrophic factors, such as brain derived neurotrophic factor. These findings raise the possibility that regulation of neural plasticity in specific neuronal circuits is integrally involved in the therapeutic intervention of mood disorders. Atypical antipsychotic drugs, including clozapine and olanzapine, are also effective for the treatment of bipolar disorder, and are used as add-on medication for unipolar depression. The possibility that these atypical antipsychotic drugs also influence the molecular determinants of synaptic plasticity that are involved in the response to drugs used for the treatment of mood disorders, is discussed.
 ...
PMID:Synaptic plasticity and mood disorders. 1198 93

The barrel cortex has yielded a wealth of information about cortical plasticity in recent years. Barrel cortex is one of the few cortical areas studied so far where plasticity can be examined from birth through to adulthood. This review looks at plasticity mechanisms in three periods of life: early post-natal development, adolescence and adulthood. Separate consideration is given to depression and potentiation mechanisms. Plasticity can be induced in barrel cortex by whisker deprivation. Single whisker experience leads to expansion of the area of cortex responding to the spared whisker. In early post-natal life, plasticity occurs in thalamocortical pathways, while later in adolescence, intracortical pathways become more important. Ablation of the spared whisker's barrel prevents expression of plasticity in the cortex. A row of lesions between the spared and an adjacent barrel prevents expression of plasticity in the adjacent barrel. This evidence, together with latency of response data and an analysis of pathways capable of inducing long-term potentiation (LTP) within barrel cortex, leads to the view that horizontal and/or diagonal pathways between barrels are responsible for plasticity expression. The mouse has become the most commonly mutated mammalian species and has a well-developed barrel cortex. Therefore, mutations can be used to study the role of particular molecules in experience-dependent plasticity of barrel cortex. Through this work, it has become clear that the major post-synaptic density protein, alpha-CaMKII, and its T286 autophosphorylation site are essential for experience-dependent plasticity. This points to a major role for excitatory transmission in cortical plasticity and raises the possibility that LTP like mechanisms are involved. Furthermore, transgenic mice carrying a reporter gene for CRE have provided evidence that CRE-mediated gene expression is also involved in barrel cortex plasticity. This view is supported by studies on alpha/delta CREB knockouts, and provides a starting point for studying the role of gene expression in experience-dependent cortical plasticity.
 ...
PMID:Anatomical pathways and molecular mechanisms for plasticity in the barrel cortex. 1203 5

The regulation of gene expression has been implicated in the etiology and treatment of depression. Transcription factors serve as the intermediates between intracellular cascades and gene expression, and may therefore be involved in the pathophysiology and pharmacotherapy of depression. We and others have previously reported an increase in the phosphorylation of the transcription factor cAMP response element binding protein (CREB) by antidepressants, alongside brain region-specific alterations in pCREB by stress. In the present study, we examined the expression of another member of the CREB/ATF family of transcription factors, ATF2, in the brains of rats chronically treated with two different antidepressants, and in rats 4 months after their exposure to prolonged stress. ATF2 phosphorylation was decreased by antidepressants and increased at the aftermath of prolonged stress, specifically in the frontal cortex. We also examined ATF2 expression in the ventral parieto-occipital region of post-mortem human brains of normal controls, depressed, bipolar, and schizophrenic patients, obtained from the Stanley Foundation Brain Consortium. No alterations were observed in the levels of ATF2. However, in the depressed group, the pATF2 levels were higher in unmedicated compared to medicated patients, suggesting an antidepressant-induced reduction in pATF2. We discuss the possible role of ATF2 in depression, and propose that an interplay between ATF2 and CREB, and possibly other transcription factors, determines the final gene expression pattern in the etiology and treatment of depression.
 ...
PMID:ATF2, a member of the CREB/ATF family of transcription factors, in chronic stress and consequent to antidepressant treatment: animal models and human post-mortem brains. 1464 83

Omega-3 fatty acids have been the subject of volumes of international research, the results of which indicate these substances may have therapeutic value in a number of medical conditions. An emerging area of research is examining the neurobehavioral aspects of omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and the critical role of these essential fats in the functioning of the central nervous system. Investigations have linked omega-3 fatty acids to a number of neuropsychiatric disorders, including depression. The purpose of this article is to examine the possible mechanisms of action and potential clinical value of omega-3 fatty acids in major depression. A novel mechanism involving omega-3 modulation of cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) is proposed.
 ...
PMID:Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression. 1465 68

Depression is a clinically and biologically heterogeneous disease that is one of the most prevalent and costly psychiatric disorders. It is the leading cause of disability regarding job performance and burden on family members in the United States and worldwide. Although the therapeutic efficacy of antidepressant drugs has been recognized for years, the exact molecular mechanisms of action remain elusive, making the systematic approach to the development of new drugs difficult. The acute increases in levels of monoamines brought about by various classes of antidepressants cannot account for the requirement of repeated, chronic administration for up to 2-6 wk before treatment benefits become evident. Furthermore, despite their efficacy, current antidepressant drugs improve symptoms in only 60% of patients treated. The development of new and better therapies depends on a thorough understanding of the neurobiology of depression and the molecular mechanisms underlying antidepressant drug action. Early studies focusing on alterations in the levels of receptors and second messengers helped define the important signaling pathways initiated by these drugs, whereas recent molecular studies suggested that long-term adaptations in cellular signaling mechanisms may be required for the onset and/or maintenance of antidepressant effects. Attention has now focused on downstream targets of Ca++ and cyclic adenosine monophosphate (cAMP) in the cell, such as the activation of transcription factors. This article discusses the transcription factor cAMP response element binding protein and a related protein, cyclic AMP response element modulator, and their roles as molecular mediators of antidepressant action.
 ...
PMID:Regulation of antidepressant activity by cAMP response element binding proteins. 1547 24

Major depressive disorder is a severe clinical problem across the globe, with a lifetime risk of 10%-30% for women and 7%-15% for men. The World Health Organization ranks major depression at the top of the list in terms of disease burden, and this burden is expected to rise in the next decade as the prevalence of the disorder grows. Since the late 1950s, a wide range of antidepressant medications targeting the monoamine systems has been available to alleviate the symptoms of major depressive disorder. Although widely prescribed, such antidepressant medications are accompanied by a delay in effectiveness, as well as varied side effects. Therefore, further characterization of the biological mechanisms behind their function is crucial for the development of new and more effective treatments. One protein that could serve as a convergence point for multiple classes of antidepressant drugs is the transcription factor CREB (cyclic adenosine monophosphate response element binding protein). CREB is upregulated by chronic antidepressant treatment, and increasing CREB levels in rodent models results in antidepressant-like behaviors. Furthermore, postmortem studies indicate that CREB levels are increased in subjects taking antidepressants at the time of death. However, not all antidepressants increase CREB levels and/or activity, and reducing CREB levels in some brain regions also results in antidepressant-like behaviors. This review attempts to consolidate the information relevant to the structure and function of the CREB protein and describe how this relates to the mechanism of antidepressant drugs. Animal models in which CREB function is enhanced, by overexpression of the protein, or reduced, by expression of mutant forms of the protein or through gene deletion experiments, are summarized in terms of identifying a role for CREB in behavioral responses in depression tests that were originally designed to evaluate antidepressant efficacy. Human postmortem and genetic studies that implicate CREB in depression and antidepressant efficacy are also discussed.
 ...
PMID:The role of CREB in depression and antidepressant treatment. 1645 82

Transforming growth factor beta-1 (TGF-beta1) plays important roles in the early development of the nervous system and has been implicated in neuronal plasticity in adult organisms. It induces long-term increases in sensory neuron excitability in Aplysia as well as a long-term enhancement of synaptic efficacy at sensorimotor synapses. In addition, TGF-beta1 acutely regulates synapsin phosphorylation and reduces synaptic depression induced by low-frequency stimuli. Because of the critical role of MAPK in other forms of long-term plasticity in Aplysia, we examined the role of MAPK in TGF-beta1-induced long-term changes in neuronal excitability. Prolonged (6 h) exposure to TGF-beta1 induced long-term increases in excitability. We confirmed this finding and now report that exposure to TGF-beta1 was sufficient to activate MAPK and increase nuclear levels of active MAPK. Moreover, TGF-beta1 enhanced phosphorylation of the Aplysia transcriptional activator cAMP response element binding protein (CREB)1, a homologue to vertebrate CREB. Both the TGF-beta1-induced long-term changes in neuronal excitability and the phosphorylation of CREB1 were blocked in the presence of an inhibitor of the MAPK cascade, confirming a role for MAPK in long-term modulation of sensory neuron function.
 ...
PMID:TGF-beta1-induced long-term changes in neuronal excitability in aplysia sensory neurons depend on MAPK. 1661 79


1 2 3 4 5 6 Next >>