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)

The effects of the pro-inflammatory cytokine interleukin-18 (IL-18) were investigated on both normal and isolated N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory post synaptic potentials (fEPSP) and on the induction of long-term potentiation (LTP) in the rat dentate gyrus in vitro. Bath perfusion with IL-18 (100 ng/ml) for 20 min prior to high-frequency stimulation had no significant effect on baseline synaptic transmission or paired pulse depression, but did impair the induction of LTP (115.7+/-8.8% versus 150.8+/-8.1% in vehicle control slices, n=6, P<0.05 at 60 min). Further analysis demonstrated that IL-18 significantly depressed the amplitude of pharmacologically isolated NMDA receptor-mediated fEPSP (NMDA-fEPSP; 77.4+/-4.3% of baseline compared to controls at 1 h; P<0.05, n=7), an effect that may underlie the impairment of LTP by IL-18. This action of IL-18 on LTP and NMDA-fEPSPs was attenuated in full by pretreatment of slices with exogenously applied IL-1 receptor antagonist (IL-1ra, 100 ng/ml), the naturally occurring antagonist of IL-1 type 1 receptors. This ability of IL-1ra to block the inhibitory effects of IL-18 is likely to be receptor-specific as no reversal of the tumour necrosis factor-alpha-induced inhibition of LTP was seen with IL-1ra administration (110.7+/-5.4% versus tumour necrosis factor-alpha-treated slices; 107.4+/-8.7%, P=0.6, n=6). These are the first experiments providing evidence of a direct neuromodulatory role for IL-18 in synaptic plasticity.
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PMID:The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro. 1173 33

Interleukin 1 receptor accessory protein (IL-1RAcP) is an essential signal-transducing component of the IL-1 receptor type I. The recent availability of IL-1RAcP-deficient (KO) mice allows to study the in vivo function of IL-1RAcP. Animals were injected intraperitoneally with rat recombinant IL-1beta (200 ng/mouse), lipopolysaccharide (LPS, 5 microg/mouse), or subjected to 1-hour restraint stress. Neuroendocrine and immune parameters were measured 2 h after IL-1 or LPS injection or just after restraint. In wild-type controls, IL-1 and LPS activated the hypothalamic-pituitary-adrenal axis and increased plasma IL-6. In KO mice, the plasma levels of corticosterone and IL-6 increased after LPS, but not after rat recombinant IL-1beta. The LPS-induced depression of the lymphoproliferation was similar in wild-type and KO mice. Finally, the 1-hour restraint was able to increase the plasma levels of corticosterone in KO mice. These results show that IL-1RAcP is essential for physiological activities of peripheral IL-1, as it was previously demonstrated for those of brain IL-1. However, using IL-1RAcP KO mice, we were unable to demonstrate a specific role of endogenous IL-1 during LPS-induced inflammation. Moreover, stress-induced activation of the hypothalamic-pituitary-adrenal axis may occur in the absence of the IL-1-transducing receptor, IL-1RAcP.
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PMID:Physiological significance of the interleukin 1 receptor accessory protein. 1184 85

This review article integrates empirical findings from various scientific disciplines into a proposed psychoneuroimmunological (PNI) model of the acute coronary syndrome (ACS). Our starting point is an existing, mild, atherosclerotic plaque and a dysfunctional endothelium. The ACS is triggered by three stages. (1) Plaque instability: Pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha) and chemoattractants (MCP-1, IL-8) induce leukocyte chemoattraction to the endothelium, and together with other triggers such as the CD40L-CD40 co-stimulation system activate plaque monocytes (macrophages). The macrophages then produce matrix metalloproteinases that disintegrate extra-cellular plaque matrix, causing coronary plaque instability. Acute stress, hostility, depression and vital exhaustion (VE) have been associated with elevated pro-inflammatory cytokines and leukocyte levels and their recruitment. (2) Extra-plaque factors promoting rupture: Neuro-endocrinological factors (norepinephrine) and cytokines induce vasoconstriction and elevated blood pressure (BP), both provoking a vulnerable plaque to rupture. Hostility/anger and acute stress can lead to vasoconstriction and elevated BP via catecholamines. (3) Superimposed thrombosis at a ruptured site: Increases in coagulation factors and reductions in anticoagulation factors (e.g. protein C) induced by inflammatory factors enhance platelet aggregation, a key stage in thrombosis. Hostility, depression and VE have been positively correlated with platelet aggregation. Thrombosis can lead to severe coronary occlusion, clinically manifested as an ACS. Thus, PNI processes might, at least in part, contribute to the pathogenesis of the ACS. This chain of events may endure due to lack of neuroendocrine-to-immune negative feedback stemming from cortisol resistance. This model has implications for the use of psychological interventions in ACS patients.
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PMID:Molecular and cellular interface between behavior and acute coronary syndromes. 1223 62

Macrophages produced proinflammatory cytokines and inflammatory responses can cause many symptoms of depression, including direct stimulation of the HPA axis and secretion of cortisol. In depressed patients, hypercortisolism has been well described as one of the major symptoms and also as the cause for hippocampal atrophy and memory impairment. In this paper, the relationships between thymectomy, increased IL-1 levels, and changes in corticosterone and neurotransmitter concentrations in rats are discussed, as well as their implications for memory impairments and depression. In thymectomized rats, deficits in both spatial and fear conditioned memory have been observed. Thymectomy decreases noradrenaline and dopamine levels, and increases serotonergic neurotransmission in limbic areas, without affecting corticosterone concentrations. In a depression model, thymopeptides or IL-2 treatment significantly attenuated changes in behavior, lymphocyte proliferation and neurotransmitters caused by bulbectomy. The reduction of thymic functions may increase IL-1 synthesis. Central IL-1beta administration impairs rat's spatial memory in the Morris water maze and 8 arms radial maze, but enhances conditioned memory in the passive avoidance. These changes can be reversed by either IL-1 receptor antagonist or a glucocorticoid receptor antagonist (RU 486). Furthermore, IL-1-induced changes in some neurotransmitter systems are similar to those observed in thymectomized rats. However, both acute and sub-chronic IL-1 administration increases plasma corticosterone concentrations. Together, these findings suggest that changes in the function of the thymus gland may play an important role in the unbalance between macrophages, cytokines, and lymphocytes, which induces neurotransmitter and neuroendocrine changes, and memory disturbances in depressive illness.
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PMID:The effect of thymectomy and IL-1 on memory: implications for the relationship between immunity and depression. 1240 69

The objective of the present study was to investigate the relation between adipose tissue polyunsaturated fatty acids, an index of long-term or habitual fatty acid dietary intake, and depression. The sample consisted of 247 healthy adults (146 males, 101 females) from the island of Crete. The number of subjects with complete data on all variables studied was 139. Subjects were examined at the Preventive Medicine and Nutrition Clinic of the University of Crete. Depression was assessed through the use of the Zung Self-rating Depression Scale. Mildly depressed subjects had significantly reduced (-34.6%) adipose tissue docosahexaenoic acid (DHA) levels than non-depressed subjects. Multiple linear regression analysis indicated that depression related negatively to adipose tissue DHA levels. In line with the findings of other studies, the observed negative relation between adipose tissue DHA and depression, in the present study, appears to indicate increasing long-term dietary DHA intakes with decreasing depression. This is the first literature report of a relation between adipose tissue DHA and depression. Depression has been reported to be associated with increased cytokine production, such as IL-1, IL-2, IL-6, INF-gamma and INF-alpha. On the other hand, fish oil and omega-3 fatty acids have been reported to inhibit cytokine synthesis. The observed negative relation between adipose DHA and depression, therefore, may stem from the inhibiting effect of DHA on cytokine synthesis.
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PMID:Depression and adipose essential polyunsaturated fatty acids. 1244 91

Administration of the cytokines interferon-alpha and interleukin-2 is used for the treatment of various disorders, such as hepatitis C and various forms of cancer. The most serious side-effects are symptoms associated with depression, including fatigue, increased sleepiness, irritability, loss of appetite as well as cognitive changes. However, great differences exist in the prevalence of the development of depressive symptoms across studies. Differences in doses and duration of therapy may be sources of variation as well as individual differences of patients, such as a history of psychiatric illness. In addition, sensitization effects may contribute to differential responses of patients to the administration of cytokines. In animals administration of pro-inflammatory cytokines induces a pattern of behavioural alterations called 'sickness behaviour' which resembles the vegetative symptoms of depression in humans. Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor tryptophan in depressed people support a role for 5-HT in the development of depression. In addition, evidence exists for a dysregulation of the noradrenergic system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression. Some mechanisms exist which make it possible for cytokines to cross the blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha, IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the HPA axis. Altogether, administration of cytokines may induce alterations in the brain resembling those found in depressed patients, which leads to the hypothesis that cytokines induce depression by their influence on the 5-HT, noradrenergic and HPA system.
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PMID:The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. 1246 36

In many forms of cardiomyopathic left ventricular (LV) dysfunction, there is a rapid myocardial expression of pro-inflammatory cytokines such as interleukin 1, interleukin 6 and tumour necrosis factor-alpha (TNF-alpha) which mediate, via specific receptors, various processes such as gene expression, cell growth or apoptosis. In the initial stages of myocarditis, the myocardial expression of proinflammatory cytokines appears to be part of an inflammatory process. In many other conditions such as ischaemic cardiomyopathy and chronic LV pressure or volume overload, myocardial expression of proinflammatory cytokines is triggered by an elevation of LV wall stress. Myocardial expression of cytokines contributes to depression of contractile performance and adverse LV remodelling. Cytokine-induced depression of contractile performance appears to result from sphingosine production, which interferes with myocardial calcium handling. In transgenic mice, the rate of progression of LV dilatation appears to correlate with the intensity of myocardial TNF-alpha overexpression. In heart failure patients, cytokine concentrations are elevated not only in the myocardium but also in plasma. Cytokines are, therefore, responsible not only for autocrine and paracrine signalling within the myocardium but also for endocrine signalling throughout the body, especially affecting striated muscle mass with induction of muscle wasting and cachexia. The source of cytokine production in heart failure remains uncertain and several mechanisms have been proposed including endotoxin-induced immune activation due to bowel oedema, myocardial production due to haemodynamic overload and peripheral extramyocardial production due to tissue hypoperfusion and hypoxia. The latter seems to be the most likely mechanism, possibly modulated by the presence of bacterial endotoxins released from the gut. Numerous drugs have meanwhile been shown to influence this cardioinflammatory response to heart failure either by reducing basal levels of cytokines (e.g. amlodipine, pentoxifylline, beta-blockers) or by reducing endotoxin-induced cytokine gene expression (e.g. ouabain, amiodarone, adenosine, angiotensin converting enzyme inhibitors, angiotensin II-receptor blockers). Direct blockade of the deleterious actions of elevated plasma levels of cytokines recently became possible through intravenous infusion of a soluble TNF-alpha receptor fusion protein, which resulted in an increase in exercise tolerance and LV performance.
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PMID:Cytokines and heart failure. 1263 74

In mice, lateralization as assessed by paw preference represents a behavioral trait linked to immune reactivity and stress susceptibility. Right-pawed mice are more reactive to stress than left-pawed animals when brain metabolism, activation of the corticoid axis, and depression of lymphoproliferation are studied. Since stress responses include cytokine production, we address the possibility that lateralization influences the production of cytokines--especially interleukin (IL)-1--responsible for depression of lymphoproliferation and activation of the corticoid axis. Increased plasma IL-1 level that may be considered as a stress marker, was observed in right- but not in left-pawed mice submitted to a 4 h-restraint. Likewise, plasma levels were greater in right- than in left-pawed animals 2 h after the administration of a low dose of lipopolysaccharides (LPS). By contrast, there was no lateralization effect in restraint-induced plasma level of IL-6 or in the LPS-induced increase in plasma IL-10. Prazosin, an alpha1/alpha2 adrenoreceptor antagonist, drastically increased plasma IL-10 induced by LPS, reduced plasma levels of IL-1 and abolished the effect of lateralization observed after LPS alone. This suggests that alpha-adrenergic modulation of IL-1 production depends on lateralization through mechanisms that need further investigation.
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PMID:Cytokine stress responses depend on lateralization in mice. 1263 2

Autonomic functions, such as increased sympathetic and parasympathetic activity and the brain's suprachiasmatic nucleus, higher nervous centres, depression, hostility and aggression appear to be important determinants of heart rate variability (HRV), which is, itself, an important risk factor of myocardial infarction, arrhythmias, sudden death, heart failure and atherosclerosis. The circadian rhythm of these complications with an increased occurrence in the second quarter of the day may be due to autonomic dysfunction as well as to the presence of excitatory brain and heart tissues. While increased sympathetic activity is associated with increased levels of cortisol, catecholamines, serotonin, renin, aldosterone, angiotensin and free radicals; increased parasympathetic activity may be associated with greater levels of acetylecholine, dopamine, nitric oxide, endorphins, coenzyme Q10, antioxidants and other protective factors. Recent studies indicate that hyperglycemia, diabetes, hyperlipidemia, ambient pollution, insulin resistance and mental stress can increase the risk of low HRV. These risk factors, which are known to favour cardiovascular disease, seem to act by decreasing HRV. There is evidence that regular fasting may modulate HRV and other risk factors of heart attack. While exercise is known to decrease HRV, exercise training may not have any adverse effect on HRV. In a recent study among 202 patients with acute myocardial infarction (AMI), the incidence of onset of chest pain was highest in the second quarter of the day (41.0%), mainly between 4.0-8.0 AM, followed by the fourth quarter, usually after large meals (28.2%). Emotion was the second most common trigger (43.5%). Cold weather was a predisposing factor in 29.2% and hot temperature (> 40 degrees celsius) was common in 24.7% of the patients. Dietary n-3 fatty acids and coenzyme Q10 have been found to prevent the increased circadian occurrence of cardiac events in our randomized controlled trials, possibly by increasing HRV. We have also found that n-3 fatty acids plus CoQ can decrease TNF-alpha and IL-6 in AMI which are pro-inflammatory agents. There is evidence that dietary n-3 fatty acids canenhance hippocampal acetylecholine levels, which may be protective. Similarly, the stimulation of the vagus nerve may inhibit TNF synthesis in the liver and acetylecholine, the principal vagal neurotransmitter, significantly attenuates the release of pro-inflammatory cytokines TNF-alpha, interleukin 1,6 and 18, but not the anti-inflammatory cytokine IL-10 in experiments. Therefore, any agent which can enhance brain acetylecholine levels, may be used as a therapeutic agent in protecting the suprachiasmatic nucleus, higher nervous centres, vagal activity and sympathetic nerve activity which are known to regulate the body clock and HRV and the risk of SCD and heart attack.
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PMID:Brain-heart connection and the risk of heart attack. 1265 78

In recent years, there has been increasing recognition that pro-inflammatory cytokines play a role in behavioral and physiological alterations produced by exposure to psychological stressors. Indeed, increases in central IL-1 production have been observed following stressors such as inescapable tailshock and social isolation, while no changes in IL-1 have been observed following other stressors (e.g., exposure to a predator). The goal of the following work was to establish whether exposure to the forced swim test (FST), a commonly used animal model of behavioral despair/depression, leads to an increase in central or peripheral production of IL-1. Briefly, adult male Sprague-Dawley rats (n=8 per group) were forced to swim for 15-30 min (25 degrees C) and killed at various intervals (ranging from immediately to 24 h) following stressor termination. Brains (hippocampus, hypothalamus, posterior cortex) and multiple peripheral tissues (pituitary, adrenals, spleen, plasma) were then dissected and frozen for subsequent measurement of IL-1 using a commercially available enzyme-linked immunosorbent assay. No observable increases in IL-1 were found in rats that were forced to swim acutely, or in rats that were re-exposed to the forced swim stressor 24 h later. These data suggest that exposure to forced swim does not lead to an increase in central production of IL-1, suggesting that the central IL-1 system is unlikely to play a role in mediating behavioral consequences of this stressor. However, these data do not exclude the possibility that other pro-inflammatory cytokines (such as IL-6 and TNF-alpha) might be produced in response to forced swim exposure.
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PMID:Exposure to forced swim stress does not alter central production of IL-1. 1271 Oct 78


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