Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The spontaneous and induced interferon (IFN) production in whole blood cultures was examined in 45 psychiatric inpatients and in 65 normal controls. Among inpatients there were 32 who were chronic schizophrenics (14 women, 18 men) and 13 who were severely depressed (11 women, 2 men). The analysis of the pooled results of assays in the heterogeneous population showed that leukocytes of the psychiatric patients produced significantly lower levels of IFN after stimulation with virus (NDV), lipopolysaccharide (LPS), and IFN spontaneously released without the inducers that control cells. In contrast, there was no difference between the psychiatric patients and controls in IFN response to phytohemagglutinin and phorbol myristate acetate (PHA + PMA). The results apparently confirmed observations made by Moises et al (1985) and Katila et al (1989). We have also tested our hypothesis that the statistics may mask the individual pattern of IFN response related to the specific psychiatric diagnosis, however. In fact, in the group of chronic schizophrenics we have found either high or low responders to all IFN inducers (NDV, PHA + PMA and LPS). Furthermore, the patients with high IFN response had dominant positive symptoms of schizophrenia (delusions, hallucinations, bizarre behavior and thought disorder). Whereas, in the patients with low IFN response the negative symptoms prevailed (asociality or withdrawal, flat affect, attention impairment, abolition or apathy). In plasma samples of schizophrenics, factors were detected that transferred a hypersensitivity to the IFN inducers to normal donor leukocytes. For instance, in leukocytes cultured in the presence of plasma from schizophrenics, there were 71% of high IFN responders after stimulation with NDV, versus 26% of high IFN responders in the presence of plasma from normal controls. We suggest that the factors may belong to the class of opioid peptides, which interact with the production of cytokines including IFNs.
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PMID:Interferon responses in schizophrenia and major depressive disorders. 751 91

Prenatal exposure to infection appears to increase the risk of schizophrenia and other neurodevelopmental disorders. We have hypothesized that cytokines, generated in response to maternal infection, play a key mechanistic role in this association. E16 timed pregnancy rats were injected i.p. with Escherichia coli lipopolysaccharide (LPS) to model prenatal exposure to infection. Placenta, amniotic fluid and fetal brains were collected 2 and 8h after LPS exposure. There was a significant treatment effect of low-dose (0.5mg/kg) LPS on placenta cytokine levels, with significant increases of interleukin (IL)-1beta (P<0.0001), IL-6 (P<0.0001), and tumor necrosis factor-alpha (TNF-alpha) (P=0.0001) over the 2 and 8h time course. In amniotic fluid, there was a significant effect of treatment on IL-6 levels (P=0.0006). Two hours after maternal administration of high-dose (2.5mg/kg) LPS, there were significant elevations of placenta IL-6 (P<0.0001), TNF-alpha (P<0.0001), a significant increase of TNF-alpha in amniotic fluid (P=0.008), and a small but significant decrease in TNF-alpha (P=0.035) in fetal brain. Maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain.
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PMID:Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. 1116 42

Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge- peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia.
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PMID:Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. 1179 May 16

There is some evidence that the pathophysiology of schizophrenia is related to changes in the innate and adaptive immune systems. In an attempt to define a potential immunological dysfunction in schizophrenia, we measured the serum levels of several cytokines in the sera of 24 patients with paranoid schizophrenia and investigated the cytokine production in whole blood assays after stimulation in vitro with virus (Newcastle disease), phytohemagglutinin (PHA) or bacterial lipopolysaccharide (LPS) and compared them with healthy, normal controls. A significant increase of interleukin 6 (IL-6), IL-8 and interferon gamma (IFN-gamma) levels, but a decreased L-10 level were observed in the sera of patients with schizophrenia. No significant changes in the serum levels of IL-2, IL-4, IFN-alpha and tumor necrosis factor alpha (TNF-alpha) were detected in these patients. When cytokine production in vitro was examined, a significant defect in PHA-induced IL-2, L-4 and IFN-gamma, and in virus-induced IFN-alpha production, but no significant alterations in LPS-induced IL-6, IL- 10 and TNF-alpha production were observed. In summary, increased serum levels of some cytokines such as IL-6, IL-8 and IFN-gamma indicate an activation of the inflammatory response in schizophrenia, while the in vitro assay indicates significant changes in the Th1 (decreased production of 1L-2 and IFN-gamma) and Th2 (decreased production of IL-4) cell system responses. The role of the defective EFN-alpha production in the regulation of the imbalance between Th1 and Th2 cell system responses is suggested.
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PMID:Investigation of serum cytokine levels and cytokine production in whole blood cultures of paranoid schizophrenic patients. 1181 38

Previously, we have found that some antipsychotic drugs are able to inhibit glucocorticoid receptor (GR)-mediated gene transcription. Since these drugs are known not only to inhibit hypothalamic-pituitary-adrenal (HPA) axis activity, but also to modulate the immunological system, the aim of the present study was to compare the effect of sulpiride and clozapine on GR function under basal culture conditions and during activation by lipopolysaccharide (LPS). The effect of clozapine and sulpiride alone and with LPS, the immune system activator, on glucocorticoid-mediated gene transcription was investigated in fibroblast cells, stably transfected with a mouse mammary tumor virus--chloramphenicol acetyltransferase plasmid (LMCAT cells). Treatment of the cells with clozapine (3-10 microM) for 2 days significantly and in concentration-dependent manner decreased the chloramphenicol acetyltransferase (CAT) activity, while sulpiride (1, 3, 5 and 10 microM) was without any effect. LPS (1 microg/ml) given alone inhibited the corticosterone-induced gene transcription by ca. 35%. Clozapine (3, 5 and 10 microM) inhibited the effect of LPS (1 microM), while sulpiride, which alone had no effect on GR function, enhanced LPS (1 microM) action. The obtained results indicate that inhibition of GR-mediated gene transcription by LPS and clozapine can be a mechanism by which these compounds blocked some effects induced by glucocorticoids. Opposite effect of clozapine and sulpiride on LPS action may result from their distinct effect on activity of some kinases involved in regulation of GR transcriptional function and may determine their utility in the treatment of schizophrenia with or without immune system activation.
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PMID:Opposite effects of clozapine and sulpiride on the lipopolysaccharide-induced inhibition of the GR-mediated gene transcription in fibroblast cells. 1473 Jan 15

Perinatal infections are a risk factor for fetal neurological pathologies, including cerebral palsy and schizophrenia. Cytokines that are produced as part of the inflammatory response are proposed to partially mediate the neurological injury. This study investigated the effects of intraperitoneal injections of lipopolysaccharide (LPS) to pregnant rats on the production of cytokines and stress markers in the fetal environment. Gestation day 18 pregnant rats were treated with LPS (100 microg/kg body wt i.p.), and maternal serum, amniotic fluid, placenta, chorioamnion, and fetal brain were harvested at 1, 6, 12, and 24 h posttreatment to assay for LPS-induced changes in cytokine protein (ELISA) and mRNA (real-time RT-PCR) levels. We observed induction of proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) as well as the anti-inflammatory cytokine IL-10 in the maternal serum within 6 h of LPS exposure. Similarly, proinflammatory cytokines were induced in the amniotic fluid in response to LPS; however, no significant induction of IL-10 was observed in the amniotic fluid. LPS-induced mRNA changes included upregulation of the stress-related peptide corticotropin-releasing factor in the fetal whole brain, TNF-alpha, IL-6, and IL-10 in the chorioamnion, and TNF-alpha, IL-1 beta, and IL-6 in the placenta. These findings suggest that maternal infections may lead to an unbalanced inflammatory reaction in the fetal environment that activates the fetal stress axis.
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PMID:Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain. 1498 88

An increased incidence of schizophrenia has been associated with several perinatal insults, most notably maternal infection during pregnancy and perinatal hypoxia. This study used a rat model to directly test if maternal exposure to bacterial endotoxin (lipopolysaccharide, LPS) during pregnancy alters behaviors relevant to schizophrenia, in offspring at adulthood. The study also tested if postnatal anoxia interacted with gestational LPS exposure to affect behavior. At adulthood, offspring from dams administered LPS on days 18 and 19 of pregnancy showed significantly increased amphetamine-induced locomotion, compared to offspring from saline-treated dams. A period of anoxia on postnatal day 7 had no effect on amphetamine-induced locomotion and there was no interaction between effects of gestational LPS and postnatal anoxia on this behavior. Offspring from LPS-treated dams also showed enhanced acoustic startle responses as adults, compared to offspring from saline-treated dams. In offspring tested for pre-pulse inhibition (PPI) of acoustic startle and for apomorphine modulation of PPI, no effects of either gestational LPS or of postnatal anoxia and no interactions between LPS and anoxia were observed. It is concluded that maternal LPS exposure during pregnancy in the rat may be a useful model to study mechanisms responsible for effects of maternal infection on behaviors relevant to schizophrenia, in offspring.
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PMID:Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring. 1500 40

Alpha 7 nicotinic acetylcholine receptors are involved in learning and memory, and are implicated in the pathology of Alzheimer's disease and schizophrenia. Detection of alpha7 subunits can be accomplished via immunodetection or alpha-bungarotoxin-binding techniques. Standard protocols for immunohistochemistry and Western blotting were followed using several commercially available antibodies. Various mice were evaluated, including non-transgenics, APP, PS1, APP+PS1, and alpha7 knockouts. Initial results with amyloid-depositing mice revealed alpha7 immunolabeled astrocytes, in addition to expected neuronal staining. Subsequent studies with intrahippocampal injections of lipopolysaccharide (LPS) into alpha7 knockout mice showed that both neuronal and astrocytic labeling by alpha7 antibodies was nonspecific. On Western blots of mouse brain proteins, none of the bands detected with antibodies directed against alpha7 subunits diminished in the alpha7 knockout mice. Although LPS-related changes in the expression of some bands were found, these also were unaffected by the alpha7 genotype of the mice. In general, the Western staining patterns for these antibodies revealed few overlapping bands. These immunodetection data are in contrast to genotyping results and mRNA analyses that confirmed the disruption of the alpha7 allele and lack of alpha7 message in the knockouts. These findings suggest caution in interpreting results when using several commercially available alpha7 nicotinic receptor antibodies.
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PMID:Biochemical and histochemical evidence of nonspecific binding of alpha7nAChR antibodies to mouse brain tissue. 1538 83

It has been hypothesized that dysregulations of the immune system and glucocorticoid receptor (GR) function are involved in the pathogenesis of schizophrenic disorders. Previously, we found that among antipsychotics, chlorpromazine most potently inhibited GR function under in vitro conditions. In order to study a role of the some immune system mediators in this process, we investigated the effect of lipopolysaccharide (LPS) on chlorpromazine-induced changes in GR-mediated gene transcription in fibroblast cells, stably transfected with mouse mammary tumor virus promoter (LMCAT cells). Two days of incubation of the cells with LPS (1 and 5 microg/ml) and chlorpromazine (3-30 microM) inhibited the corticosterone-induced gene transcription in a concentration-dependent manner. Concomitant incubation of the cells with LPS (1 microg/ml) and chlorpromazine had stronger inhibitory effect than that evoked by each compound alone. The effect of LPS, but not that of chlorpromazine, on GR function was dependent on p38 mitogen-activated protein kinase (MAPK). Moreover, LPS-stimulated proliferative activity was also p38-MAP kinase dependent, but this effect was suppressed by chlorpromazine.
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PMID:Effects of lipopolysaccharide and chlorpromazine on glucocorticoid receptor-mediated gene transcription and immunoreactivity: a possible involvement of p38-MAP kinase. 1558 93

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.
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PMID:The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. 1618 9


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