UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis is associated with increased production of reactive oxidant species. Oxidative and nitrosative stress can lead to activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), with subsequent loss of cellular functions. Activation of PARP may dramatically lower the intracellular concentration of its substrate, NAD thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. In addition, PARP enhances the expression of various pro-inflammatory mediators, via activation of NF-kappaB, MAP kinase and AP-1 and other signal transduction pathways. Preclinical studies in various rodent and large animal models demonstrate that PARP inhibition or PAR deficiency exerts beneficial effects on the haemodynamic and metabolic alterations associated with septic and haemorrhagic shock. Recent human data also support the role of PARP in septic shock: In a retrospective study in 25 septic patients, an increase in plasma troponin level was related to increased mortality risk. In patients who died, significant myocardial damage was detected, and histological analysis of heart showed inflammatory infiltration, increased collagen deposition, and derangement of mitochondrial criptae. Immunohistochemical staining for poly(ADP-ribose) (PAR), the product of activated PARP was demonstrated in septic hearts. There was a positive correlation between PAR staining and troponin I; and a correlation of PAR staining and LVSSW. Thus, there is significant PARP activation in animal models subjected to circulatory shock, as well as in the hearts of septic patients. Based on the interventional studies in animals and the correlations observed in patients we propose that PARP activation may be, in part responsible for the cardiac depression and haemodynamic failure seen in humans with severe sepsis. Interestingly, recent studies reveal that the protective effects of PARP inhibitors are predominant in male animals, and are not apparent in female animals. Oestrogen, by providing a baseline inhibitory effect on PARP activation, may be partially responsible for this gender difference.
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PMID:Poly (ADP-ribose) polymerase activation and circulatory shock. 1738 Jul 90

Photolysis of a caged Ca(2+) compound was used to characterize the dependence of cerebellar long-term synaptic depression (LTD) on postsynaptic Ca(2+) concentration ([Ca(2+)](i)). Elevating [Ca(2+)](i) was sufficient to induce LTD without requiring any of the other signals produced by synaptic activity. A sigmoidal relationship between [Ca(2+)](i) and LTD indicated a highly cooperative triggering of LTD by Ca(2+). The duration of the rise in [Ca(2+)](i) influenced the apparent Ca(2+) affinity of LTD, and this time-dependent behavior could be described by a leaky integrator process with a time constant of 0.6 s. A computational model, based on a positive-feedback cycle that includes protein kinase C and MAP kinase, was capable of simulating these properties of Ca(2+)-triggered LTD. Disrupting this cycle experimentally also produced the predicted changes in the Ca(2+) dependence of LTD. We conclude that LTD arises from a mechanism that integrates postsynaptic Ca(2+) signals and that this integration may be produced by the positive-feedback cycle.
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PMID:Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. 1755 26

Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.
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PMID:Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice. 1780 10

Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. However, molecular mechanisms of the rapid action are yet largely unknown. We here describe rapid modulation of representative synaptic plasticity, i.e., long-term depression (LTD), long-term potentiation (LTP) and spinogenesis, by 17beta-estradiol, selective estrogen agonists as well as endocrine disrupters. The authors demonstrated that 1-10 nM estradiol induced rapid enhancement of LTD within 1 h in not only CA1 but also CA3 and dentate gyrus (DG). On the other hand, the modulation of LTP by estradiol was not statistically significant. The total density of spines was increased in CA1 pyramidal neurons, within 2 h after application of estradiol. The total density of thorns (postsynaptic spine-like structure) was, however, decreased by estradiol in CA3 pyramidal neurons. Both the increase of spines in CA1 and the decrease of thorns in CA3 were completely suppressed by Erk MAP kinase inhibitor. Only ERalpha agonist PPT induced the same enhancement/suppression effect as estradiol on both LTD and spinogenesis in CA1 and CA3. ERbeta agonist DPN induced completely different results. ERalpha localized in spines and presynapses of principal glutamatergic neurons in CA1, CA3 and DG. The same ERalpha was also located in nuclei and cytoplasm. Identification of ERalpha was successfully performed using purified RC-19 antibody. Non-purified ERalpha antisera, however, reacted significantly with unknown proteins, resulting in wrong immunostaining different from real ERalpha distribution. An issue of 'endocrine disrupters' (1-100 nM low dose of environmental chemicals), which are artificial xenoestrogenic or anti-xenoestrogenic substances, has emerged as a social and environmental problem. Endocrine disrupters were found to significantly modulate LTD and spinogenesis. Bisphenol A (BPA) and diethylstilbestrol (DES) enhanced LTD in CA1 and CA3. The total spine density was significantly increased by BPA and DES in CA1. Most probable receptors for BPA and DES may be Ralpha; however, other receptors might also be involved.
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PMID:Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons. 1782 75

Given the array of biological changes induced by stressors, it is not surprising that these experiences may provoke a variety of illnesses. Among others things, stressors promote functional changes of neuropeptide and classical neurotransmitter systems. The peptidergic changes, for instance, include alterations of corticotropin releasing hormone, arginine vasopressin, and bombesin-like peptides at specific brain sites. Similarly some of the neurotransmitter systems influenced by stressors include GABAergic and monoamine functioning. Variations of these processes may limit neurogenesis (and dysregulation of growth factors such as BDNF) and influence cellular viability (through NFkappaB and MAP kinase pathways). As well, stressors activate the inflammatory immune system, notably the release of signaling molecules (cytokines), which may provoke many of the same neuropeptide (and other neurotransmitter) changes. By virtue of their actions on neuronal functioning, inflammatory processes may influence stress-related illness, such as depression, and may be a common denominator for the comorbidity that exists between depression and neurological conditions, including Parkinson's and Alzheimer's diseases, as well as cardiovascular-related pathology. The present report provides an overview of biological endophenotypes associated with stressors that are thought to be related to major depressive disorder and related comorbid conditions. The view is taken that synergy between stressors and inflammatory factors may promote pathological outcomes through their actions on neuropeptides and several neurotransmitters. As well, stressful events may result in the sensitization of neurochemical and cytokine processes, so that later re-exposure to these stimuli may promote rapid and exaggerated responses that favor illness recurrence.
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PMID:Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. 1834 32

Protein kinase C (PKC) is involved in synaptic remodeling, induction of protein synthesis, and many other processes important in learning and memory. Activation of neuronal protein kinase C correlates with, and may be essential for, all phases of learning, including acquisition, consolidation, and reconsolidation. Protein kinase C activation is closely tied to hydrolysis of membrane lipids. Phospholipases C and A2 produce 1,2-diacylglycerol and arachidonic acid, which are direct activators of protein kinase C. Phospholipase C also produces inositol triphosphate, which releases calcium from internal stores. Protein kinase C interacts with many of the same pathways as insulin; therefore, it should not be surprising that insulin signaling and protein kinase C activation can both have powerful effects on memory storage and synaptic remodeling. However, investigating the possible roles of insulin in memory storage can be challenging, due to the powerful peripheral effects of insulin on glucose and the low concentration of insulin in the brain. Although peripheral for insulin, synthesized in the beta-cells of the pancreas, is primarily involved in regulating glucose, small amounts of insulin are also present in the brain. The functions of this brain insulin are inadequately understood. Protein kinase C may also contribute to insulin resistance by phosphorylating the insulin receptor substrates required for insulin signaling. Insulin is also responsible insulin-long term depression, a type of synaptic plasticity that is also dependent on protein kinase C. However, insulin can also activate PKC signaling pathways via PLC gamma, Erk 1/2 MAP kinase, and src stimulation. Taken together, the available evidence suggests that the major impact of protein kinase C and its interaction with insulin in the mature, fully differentiated nervous system appears to be to induce synaptogenesis, enhance memory, reduce Alzheimer's pathophysiology, and stimulate neurorepair.
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PMID:Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. 1840 35

The neuropeptide corticotropin-releasing factor (CRF) plays a critical role in the proper functioning of the stress response system through its actions on its receptors, CRF receptor 1 (CRF1) and CRF receptor 2 (CRF2), located at multiple anatomical sites. Clinical data indicate that stress response dysfunctions, such as excessive CRF activity and hyperstimulation of CRF1, are present in a range of stress-related disorders, including depression and anxiety disorders. Our previous work along with that of other laboratories has demonstrated that mice deficient in CRF2 (CRF2-/-) display increased anxiety and depression-like behaviors. In this study, we found CRF2-/- mice display increased hippocampal levels of activated (phosphorylated) mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and ribosomal protein S6 kinases 1 (RSK1). These changes can be explained by overactive hippocampal CRF1, in view of the finding that the application of the nonselective CRF receptor antagonist [Glu(11,16)] astressin ([Glu(11,16)]Ast) into the dorsal hippocampus of mutant mice returned the levels of the phosphorylated proteins to baseline. Moreover, inhibition of the hippocampal MEK/ERK pathway with the specific MEK inhibitor U0126, decreased depression-like behaviors in the forced swim test and tail suspension test of CRF2-/- mice. Similarly, treatment with [Glu(11,16)]Ast reversed depression phenotype of CRF2-/- mice without affecting the phenotype of wild-type littermates. Our results support an involvement of CRF receptors in the development of depression, such that elevated hippocampal CRF1 activity, in the absence of CRF2, produces a depression-dominated phenotype through the activation of the MEK/ERK pathway.
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PMID:Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-deficient mice. 1884 68

Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.
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PMID:Target identification for CNS diseases by transcriptional profiling. 1892 5

Our previous study suggests that in prenatal stress model of depression glucocorticoid receptor (GR) function in adult rats is enhanced. However, the long-term consequences of stress, a causal factor in depression, on intracellular elements involved into the regulation of GR function is poorly examined. Mitogen-activated protein kinases (MAPKs), activity of which is disturbed in depression, are important regulators of GR action, so they can mediate the effect of stress on GR function. Therefore, the aim of the present study was to investigate the levels of active phosphorylated forms of extracellular signal-regulated kinases (ERK), Jun N-terminal kinases (JNK) and the p38 kinase in the hippocampus and frontal cortex in rats subjected to prenatal stress. The concentration of MAP kinase phosphatase (MKP-1, MKP-2) and protein phosphatase-2A (PP2A), which dephosphorylate all forms of MAP kinases, were also determined. During verification of the applied model of depression, we found that prenatally stressed rats displayed high level of immobility in the Porsolt test and that the administration of imipramine, fluoxetine, mirtazapine and tianeptine for 21 days normalized this parameter. Western blot study revealed that rats subjected to prenatal stress had decreased levels of p-JNK1 and p-JNK2 in the hippocampus and p-p38 in the frontal cortex, but the concentrations of p-ERK1 and p-ERK2 were not changed. Chronic treatment with imipramine inhibited the stress-induced decrease in p-JNK1/2, while imipramine, fluoxetine and mirtazapine blocked changes in p-p38. PP2A phosphatase level was higher in the hippocampus and frontal cortex in prenatally stressed animals than in control rats. Chronic treatment with antidepressant drugs attenuated the stress-induced increase in the level of this phosphatase, but had no effect on its concentration in control animals. There was no significant difference in MKP-1 and in MKP-2 levels in both brain structures between control and prenatally stressed rats. The obtained results showed that prenatal stress decreased the levels of active form of JNK and p38, but enhanced PP2A phosphatase expression and most of these changes were reversed by antidepressant drugs. Since p-JNK and p-p38 are known to inhibit GR function their lowered levels may enhance glucocorticoid action. Furthermore, the increased PP2A concentration may intensify GR action not only by inhibition of JNK and p38 phosphorylation, but also by a direct influence on the process of GR translocation.
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PMID:The decrease in JNK- and p38-MAP kinase activity is accompanied by the enhancement of PP2A phosphate level in the brain of prenatally stressed rats. 2043 22

Erk4 and Erk3 are atypical members of the mitogen-activated protein (MAP) kinase family. The high sequence identity of Erk4 and Erk3 proteins and the similar organization of their genes imply that the two protein kinases are paralogs. Recently, we have shown that Erk3 function is essential for neonatal survival and critical for the establishment of fetal growth potential and pulmonary function. To investigate the specific functions of Erk4, we have generated mice with a targeted disruption of the Mapk4 gene. We show that Erk4-deficient mice are viable and fertile and exhibit no gross morphological or physiological anomalies. Loss of Erk4 is not compensated by changes in Erk3 expression or activity during embryogenesis or in adult tissues. We further demonstrate that additional loss of Erk4 does not exacerbate the fetal growth restriction and pulmonary immaturity phenotypes of Erk3(-/-) mice and does not compromise the viability of Erk3(+/-) neonates. Interestingly, behavioral phenotyping revealed that Erk4-deficient mice manifest depression-like behavior in the forced-swimming test. Our analysis indicates that the MAP kinase Erk4 is dispensable for mouse embryonic development and reveals that Erk3 and Erk4 have acquired specialized functions through evolutionary diversification.
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PMID:Targeted inactivation of Mapk4 in mice reveals specific nonredundant functions of Erk3/Erk4 subfamily mitogen-activated protein kinases. 2095 58

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