UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is a strong interrelationship between the immune system, the central nervous system and psychological processes that are suggested to play a pivotal role in the pathogenesis of psychiatric disorders. In schizophrenia and depression, activation of the immune system has been observed repeatedly. Cytokines play a key role in immune activation. They are actively transported into the CNS, but also released from activated glia cells. Cytokines activate glia cells in the CNS to produce other cytokines, and a cascade of cytokine effects may be initiated by this mechanisms. During the past few years, the influence of the cytokines on dopaminergic, noradrenergic and serotonergic neurotransmission and also on the hormones of the hypothalamus-pituitary-adrenal axis has been elucidated. It suggests a pivotal role in psychological processes and psychiatric disorders. For example, in schizophrenia the IL-2 cerebrospinal fluid concentration shows a stronger relationship to the relapse probability than catecholamine metabolites. Although the hypersecretion of IL-2 in schizophrenia and of IL-6 in depression are suggested to play key roles for these disorders, a specificity of certain cytokines for certain psychiatric disorders seems unlikely. Psychomotor, sleep and sickness behavior are influenced by IL-1, disturbances of memory and attention by IL-2, but also by TNF-alpha. From the distribution of cytokine receptors in the CNS conclusions can be drawn regarding the influence of cytokines on psychological processes. The finding that norepinephrine stimulates activated astrocytes to produce IL-6 implies that the cytokine cascade may be activated by neuronal processes under certain conditions. This can lead to a molecular biological explanation of the influences of stress on the immune system. Lastly, influences of the cytokines on blood-brain barrier disturbances and further consequences resulting from the role of the cytokine network in the CNS are discussed.
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PMID:[Role of the cytokine network in the CNS and psychiatric disorders]. 913 17

1. Parallel to the current rapid development of new immunological methods, immune mechanisms are gaining more importance for our understanding of psychiatric disorders. The purpose of this article is to review basic and clinical investigations that elucidate the relationship between the CNS and the immune system. 2. The topical literature dealing with the interactions of immune system, neurotransmitters, psychological processes, and psychiatric disorders, especially in relation to cytokines, is reviewed. 3. An activation of the immune system in schizophrenia and depressive disorders has repeatedly been described. Cytokines, actively transported into the CNS, play a key role in this immune activation. It was recently observed that cytokines activate astrocytes and microglia cells, which in turn produce cytokines by a feedback mechanism. Moreover, they strongly influence the dopaminergic, noradrenergic, and serotonergic neurotransmission. 4. There are indications that the cascade of cytokines can be activated by neuronal processes. These findings close a theoretical gap between stress and its influence on immunity. Psychomotor, sickness behavior and sleep are related to IL-1; disturbances of memory and cognitive impairment are to IL-2, in part also to TNF-alpha. The hypersecretion of IL-2 is assumed to have a prominent influence on schizophrenia, and IL-6, on depressive disorders. 5. Although single cytokines most likely do not have a specificity for certain psychiatric disorders, a characteristic pattern of cytokine actions in the CNS, including influences of the cytokines on the blood-brain barrier, seems to play a role in psychiatric disorders. This may have therapeutic implications for the future.
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PMID:Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. 953 65

Interleukin (IL)-1, IL-2 and IL-6 influence central monoamine activity in a cytokine-specific manner. We demonstrated that whereas IL-2 increased hypothalamic and hippocampal norepinephrine (NE) utilization, and DA turnover in the prefrontal cortex, IL-6 induced profound elevations of serotonin (5-HT) and mesocortical dopamine (DA) activity in the hippocampus and prefrontal cortex [S. Zalcman, J.M. Green-Johnson, L. Murray, D.M. Nance, D.G. Dyck, H. Anisman, A. H. Greenberg, Cytokine-specific central monoamine alterations following IL-1, -2 and -6 administration, Brain Res. 643 (1994) 40-49]. IL-1, in contrast, induced a wide range of central monoamine alterations. We presently report that these cytokines also differentially influence behavior. Profound reductions in non-ambulatory and ambulatory exploration were induced in BALB/c mice following IL-1 administration. In contrast, IL-2-treated mice displayed significant increases in the time spent engaged in non-ambulatory exploration, digging, rearing (particularly the number of free rears), and in the investigation of a novel stimulus (i.e., increased number and duration of stimulus contacts). IL-6-treated mice, moreover, exhibited significant increases in the time spent engaged in ambulatory exploration, digging and rearing (particularly the number of free rears, which tended to be of short duration). Modest increases in locomotion and grooming were also observed in IL-6-treated animals. Plasma corticosterone levels did not vary significantly as a function of IL-6 treatment. Hence, cytokine-specific behavioral-activating effects were induced following administration of IL-2 and IL-6. We suggest that these effects have adaptive significance and relevance to sickness behavior; however, pathological outcomes (e.g., schizophrenia, anxious-like states, anxious depression, motor abnormalities) could develop should these cytokines be overproduced or dysregulated.
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PMID:Interleukin-2 and -6 induce behavioral-activating effects in mice. 980 16

Activation of the inflammatory response system has been related to the pathophysiology of schizophrenia by several recent studies. Schizophrenic patients have varied levels of proinflammatory cytokines, such as interleukin (IL)-1, -6, and tumor necrosis factor (TNF)alpha in their peripheral blood or cerebrospinal fluid. These cytokines can modify the metabolism of neurotransmitters, influence neural development, and IL-1 has been implicated in acute, and, on the other hand, chronic neurodegeneration. They could therefore be of primary pathogenic importance, either in the acute disease or during those stages of brain development which possibly influence the sensitivity of a person to schizophrenia in later life. The cytokine regulation of brain development and its possible neuroimmune involvement in the pathogenesis of schizophrenia has been raised. One indication of the pathogenic role of IL-1 in schizophrenia would be a demonstration of the difference between schizophrenic patients and healthy controls at the gene level. Therefore we analyzed the polymorphism of the IL-1 gene complex in 50 schizophrenic patients and in 400 healthy blood donors. The following allelisms were analyzed: IL-1beta gene: base exchange polymorphisms at the positions -511 (relative to the transcriptional start site); IL-1alpha gene: base exchange polymorphism at the position -889; IL-1 receptor antagonist (IL-1RA) gene: variable numbers of 86-base pair tandem repeats in intron 2. The frequencies of the IL-1beta (-511) allele 1, IL-1alpha (-889) allele 2, and IL-1RA allele 1 were somewhat, but not significantly, higher in the schizophrenic patients as compared to the controls. These alleles are known to be located on the same haplotype. The number of carriers of this haplotype was significantly higher in the schizophrenia patients (17/50 vs 81/400) than in the controls (P=0.026, chi2). The frequencies of this haplotype were 0.38 and 0.27, respectively (P=0.0266, chi2). The number of homozygotes of this haplotype was significantly higher in the schizophrenia patients (P=0.0006, chi2). These data suggest that the cytokine aberrations in schizophrenia are, at least partly, genetically determined.
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PMID:Polymorphisms of the interleukin-1 gene complex in schizophrenia. 1020 41

Genetic association studies were conducted among two independent cohorts of Chinese ethnicity. The samples consisted of cases and unrelated controls, ascertained from Guangzhou, China, and Singapore. The studies were prompted by our earlier report of an association between schizophrenia and HLA DQB1 alleles (HLA DQB1*0602 and HLA DQB1*0303) in the Singapore sample. Polymorphisms of HLA DQB1 and flanking markers on chromosome 6p21.3 were investigated in the first part of the study. A significant negative association with HLA DQB1*0402 was detected in the Guangzhou sample (Odds ratio, OR 0.26, 95% confidence intervals, CI 0.1, 0.6; p < 0.02, corrected for multiple comparisons). Additional analysis of the Guangzhou and Singapore samples revealed associations at three other anonymous markers flanking HLA DQB1. In the second part of the study, three polymorphisms at the Interleukin-1 gene cluster (IL-1, chromosome 2q13-q21) were investigated in both cohorts, since associations with schizophrenia have been reported in another sample. Persuasive evidence for an association at IL-1 was not detected in either sample. Our results suggest a susceptibility locus for schizophrenia in the HLA region among the Chinese, but further clarification is necessary.
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PMID:Immune related genetic polymorphisms and schizophrenia among the Chinese. 1142 78

We investigated levels of maternal cytokines in late pregnancy in relation to the subsequent development of adult schizophrenia and other psychoses in their offspring. The sample included the mothers of 27 adults with schizophrenia and other psychotic illnesses and 50 matched unaffected controls from the Providence cohort of the Collaborative Perinatal Project. Serum samples were analyzed for interleukin 1 beta (IL-1-beta), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNF-alpha) by enzyme immunoassay. Maternal levels of TNF-alpha were significantly elevated among the case series (t = 2.22, p =.04), with evidence of increasing odds of psychosis in relation to higher cytokine levels. We did not find significant differences between case and control mothers in the serum levels of IL-1, IL-2, IL-6, or IL-8. These data support previous clinical investigations reporting maternal infections during pregnancy as a potential risk factor for psychotic illness among offspring.
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PMID:Maternal cytokine levels during pregnancy and adult psychosis. 1178 7

It has been established that cytokines play a critical role in the regulation of the CNS and recent studies have suggested that dysfunctions of both pro-inflammatory (IL-1beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-1RA and IL-10) cytokines could be involved in the pathophysiology of schizophrenia. Previous studies have reported that functional polymorphisms in some cytokines genes may have important regulatory effects on such system. Therefore, the aim of the present study was to explore the possible role of the IL-1beta -511C/T and IL-1RA (86bp)(n) repeats polymorphisms in schizophrenia. A case control association study comparing genotype and allele frequencies in 346 northen Italian subjects (169 schizophrenic patients and 177 unrelated healthy volunteers) was performed. The frequencies of IL-1beta -511C and IL-1RA allele 1 (86bp)(4) are significantly higher in schizophrenic patients compared to controls (IL-1beta -511 P=0.047; IL-1RA (86bp)(n) P=0.002). Moreover our data show a protective effect of the IL-1RA allele 2 (86bp)(2) against schizophrenia (OR=0.59 95%CI:0.388-0.910; P=0.016) and this effect is enhanced by the concomitant presence of IL-1beta -511T (OR=0.48 95%CI:0.30-0.76; P=0.002). Our findings support the hypothesis that genetically determined changes in IL-1 metabolism regulation may contribute to the pathogenesis of schizophrenia confirming a role of IL-1 gene cluster in disease susceptibility.
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PMID:Association between IL-1beta -511C/T and IL-1RA (86bp)n repeats polymorphisms and schizophrenia. 1456 76

Activation of the inflammatory response system has been reported in schizophrenia. Levels of serum IL-1 receptor antagonist (IL-1ra) and soluble IL-2 receptor (sIL-2R(alpha)) were studied in 32 schizophrenic and 22 age- and sex-matched healthy subjects before and after an 8-week treatment protocol. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). At weeks 0 and 8, sIL-2R(alpha) levels were significantly higher than in the schizophrenic patients, as well as in a neuroleptic-naive subgroup, than in controls. Patients' sIL-2R(alpha) levels did not vary significantly between weeks 0 and 8. IL-1ra levels in controls did not differ significantly from those in patients at week 0 but were significantly lower at week 8. The patients' serum IL-1ra levels varied significantly between weeks 0 and 8. IL-1ra levels were significantly higher in the subgroup of neuroleptic-naive patients at week 0 than in controls. Levels of sIL-2R(alpha) at week 0 were positively correlated with PANSS positive and negative symptom scores at week 8, and levels at week 8 were positively correlated with PANSS total, positive symptom, and negative symptom scores at week 8. IL-1ra levels at week 0 were positively correlated with PANSS scores at week 8. There were positive correlations between both delta (baseline values minus endline values) IL-1ra and delta sIL-2R(alpha) levels and delta PANSS negative symptoms. The results provide evidence for immune activation in some schizophrenic patients and suggest that medication differentially affects the production of sIL-2R(alpha) and IL-1ra.
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PMID:Effect of neuroleptic administration on serum levels of soluble IL-2 receptor-alpha and IL-1 receptor antagonist in schizophrenic patients. 1584 Apr 16

Cells at the maternal-fetal interface express indoleamine 2,3 dioxygenase (IDO) to consume all local tryptophan for the express purpose of starving adjacent maternal T cells of this most limiting and essential amino acid. This stops local T cell proliferation to ultimately result in the most dramatic example of immune tolerance, acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory factors including IFNgamma, TNFalpha, IL-1, and LPS use IDO induction in responsive antigen presenting cells (APCs) also to transmit tolerogenic signals to T cells. Thus it makes sense to consider IDO induction towards tolerance for autoimmune diseases in general. Approaches to cell specific therapeutic IDO induction with NAD precursor supplementation to prevent the collateral non-T cell pathogenesis due to chronic TNFalpha-IDO activated tryptophan depletion in autoimmune diseases are reviewed. Tryptophan is an essential amino acid most immediately because it is the only precursor for the endogenous biosynthesis of nicotinamide adenine dinucleotide (NAD). Both autoimmune disease and the NAD deficiency disease pellagra occur in women at greater than twice the frequency of occurrence in men. The importance of IDO dysregulation manifest as autoimmune pellagric dementia is genetically illustrated for Nasu-Hakola Disease (or PLOSL), which is caused by a mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to psychotic symptoms rapidly progressing to presenile dementia likely due to unchecked increases in microglial IDO expression, which depletes neurons of tryptophan causing neurodegeneration. Administration of NAD precursors rescued entire mental hospitals of dementia patients literally overnight in the 1930's and NAD precursors should help Nasu-Hakola patients as well. NAD depletion mediated by peroxynitrate PARP1 activation is one of the few established mechanisms of necrosis. Chronic elevation of TNFalpha leading to necrotic events by NAD depletion in autoimmune disease likely occurs via combination of persistent IDO activation and iNOS-peroxynitrate activation of PARP1 both of which deplete NAD. Pharmacological doses of NAD precursors repeatedly provide dramatic therapeutic benefit for rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, other autoimmune diseases, and schizophrenia in either the clinic or animal models. Collectively these observations support the idea that autoimmune disease may in part be considered as localized pellagra manifesting symptoms particular to the inflamed target tissues. Thus pharmacological doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating autoimmune diseases. Distinct among the NAD precursors, nicotinic acid specifically activates the g-protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic prostaglandins PGE(2) and PGD(2). Next, PGD(2) is converted to the anti-inflammatory prostaglandin, 15d-PGJ(2). These prostaglandins exert potent anti-inflammatory activities through endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma respectively. Nicotinamide prevents type 1 diabetes and ameliorates multiple sclerosis in animal models, while nothing is known about the therapeutic potential of nicotinamide riboside. Alternatively the direct targeting of the non-redox NAD-dependent proteins using resveratrol to activate SIRT1 or PJ34 in order to inhibit PARP1 and prevent autoimmune pathogenesis are also given consideration.
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PMID:Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. 1743 Jan 13

Hypoactivity of the dorsolateral prefrontal cortex (DLPFC) during cognitive tasks is among the most consistent findings in schizophrenia. The biological factors contributing to this hypofrontality are only partially known. Previous reports have shown the influence of genes mapped to IL-1 cluster (i) in the risk to develop schizophrenia and (ii) on brain morphological abnormalities in these patients. Moreover, Interleukin-1beta (IL-1beta), encoded by IL-1B gene (IL-1 cluster, chromosome 2q13) has a key role in dopaminergic differentiation and dendrite growth in developing cortical neurons. The authors explored the role of a genetic functional polymorphism at IL-1B gene in relation to DLPFC activity. DLPFC (left and right) metabolic activity was measured in a sample of 19 DSM-IV diagnosed schizophrenic patients of Spanish origin using a procedure based on MRI/PET image fusion. During PET studies, subjects performed a contingent Continuous Performance Test aiming to activate DLPFC. Functional promoter polymorphism -511 C/T (rs16944) of IL-1B gene was genotyped in these patients. Those patients who were allele 2 (-511 T) carriers showed a lower metabolic activity in the left DLPFC with respect to patients homozygous for allele 1 (-511 C) (U = 16, z = -2.32, P = 0.02). Our results suggest that hypofrontality reported in some schizophrenic patients might be explained, at least in part, by this functional polymorphism at IL-1B gene. Genetic variants with influence on brain functionality may account for the neurocognitive heterogeneity observed in schizophrenic patients.
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PMID:Effect of interleukin-1beta gene functional polymorphism on dorsolateral prefrontal cortex activity in schizophrenic patients. 1751 Sep 51

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