| 1 | Schizophr. Res. 2002 Apr 54: 281-91 |
|---|---|
| PMID | 11950553 |
| Title | Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. |
| Abstract | There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Schizophr. Res. 2002 Apr 54: 281-91 |
| PMID | 11950553 |
| Title | Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. |
| Abstract | There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neurosci. Res. 2004 Mar 48: 345-53 |
| PMID | 15154680 |
| Title | Neonatal impact of leukemia inhibitory factor on neurobehavioral development in rats. |
| Abstract | Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Front Neuroanat 2009 -1 3: 4 |
| PMID | 19521541 |
| Title | Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons. |
| Abstract | Myelination is a highly dynamic process that continues well into adulthood in humans. Several recent gene expression studies have found abnormal expression of genes involved in myelination in the prefrontal cortex of brains from patients with schizophrenia and other psychiatric illnesses. Defects in myelination could contribute to the pathophysiology of psychiatric illness by impairing information processing as a consequence of altered impulse conduction velocity and synchrony between cortical regions carrying out higher level cognitive functions. Myelination can be altered by impulse activity in axons and by environmental experience. Psychiatric illness is treated by psychotherapy, behavioral modification, and drugs affecting neurotransmission, raising the possibility that myelinating glia may not only contribute to such disorders, but that activity-dependent effects on myelinating glia could provide one of the cellular mechanisms contributing to the therapeutic effects of these treatments. This review examines evidence showing that genes and gene networks important for myelination can be regulated by functional activity in axons. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychopharmacology (Berl.) 2009 Dec 207: 271-80 |
| PMID | 19756524 |
| Title | Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague-Dawley and Long-Evans rats. |
| Abstract | Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague-Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60-120 ms) and less sensitive to their PPI-enhancing effects at short (10-30 ms), compared with Long-Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors. The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats. PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF). As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains. Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Feb 34: 172-6 |
| PMID | 19879916 |
| Title | Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. |
| Abstract | Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family, regulates the neuronal phenotype and coordinates astrocyte, oligodendrocyte, microglia, and inflammatory cell responses. The LIF gene is located on 22q12.1-q12.2, a hot spot for schizophrenia. Three polymorphisms of the LIF gene (rs929271, rs737812, and rs929273) were examined in a case-control association study of 390 patients with schizophrenia and 410 age- and sex-matched controls. Effects of a risk genotype of LIF on cognitive domains were evaluated by the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, and Wisconsin Card Sorting Test (WCST) in 355 healthy volunteers. The LIF gene showed significant associations with schizophrenia at rs929271 and a haplotype consisting of rs929271-rs737812. After stratification by subtype of schizophrenia, the hebephrenic, but not paranoid, type was associated with the LIF gene at rs929271 (allele, P=0.014) and the haplotype (permutation P=0.013). Having the T-allele and T-carrier genotypes (TT and TG) of rs929271 were risks for hebephrenic schizophrenia, and the odds ratios were 1.38 (95% CI: 1.21-1.56) and 1.54 (95%CI: 1.19-1.98), respectively. Subjects with T-carrier genotypes made significantly more errors on the WCST compared with those without (P=0.04). The present study indicated that the LIF gene variant may produce susceptibility to hebephrenic schizophrenia and deterioration of working memory function. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 277-86 |
| PMID | 23123365 |
| Title | The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. |
| Abstract | schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning. Although novel antipsychotics have been developed, the negative and cognitive symptoms of schizophrenia are still unresponsive to pharmacotherapy. The high level of social impairment and a chronic deteriorating course suggest that schizophrenia likely has neurodegenerative characteristics. Inflammatory markers such as pro-inflammatory cytokines are well-known etiological factors for psychiatric disorders, including schizophrenia. Inflammation in the central nervous system is closely related to neurodegeneration. In addition to pro-inflammatory cytokines, microglia also play an important role in the inflammatory process in the CNS. Uncontrolled activity of pro-inflammatory cytokines and microglia can induce schizophrenia in tandem with genetic vulnerability and glutamatergic neurotransmitters. Several studies have investigated the possible effects of antipsychotics on inflammation and neurogenesis. Additionally, anti-inflammatory adjuvant therapy has been under investigation as a treatment option for schizophrenia. Further studies should consider the confounding effects of systemic factors such as metabolic syndrome and smoking. In addition, the unique mechanisms by which pro-inflammatory cytokines are involved in the etiopathology of schizophrenia should be investigated. In this article, we aimed to review (1) major findings regarding neuroinflammation and pro-inflammatory cytokine alterations in schizophrenia, (2) interactions between neuroinflammation and neurogenesis as possible neural substrates for schizophrenia, and (3) novel pharmacological approaches. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | PLoS ONE 2015 -1 10: e0129011 |
| PMID | 26043040 |
| Title | The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice. |
| Abstract | Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH-fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic-polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |