Increased Markers of Oxidative Stress and Positive Correlation Low-Grade Inflammation with Positive Symptoms in the First Episode of Schizophrenia in Drug-Naïve Patients.

Schizophrenia is a severe and chronic mental illness usually diagnosed in adolescents and young adults. Many studies indicate that oxidative stress causes membrane dysfunction and cell damage, which is implicated in the pathophysiology of schizophrenia. The purpose of our study was to evaluate oxidative stress markers (the main primary products of lipid peroxidation, lipid hydroperoxides (LOOH), and end products of lipid peroxidation, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and Ferric Reducing Ability of Plasma (FRAP)) in the plasma of patients with the first episode of schizophrenia in drug-naïve patients (22 men and 12 women aged 17-29). The control group (Ctrl) comprised 26 healthy subjects (19 men and 7 women, aged 18-30 years). The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate psychotic symptoms. Analyses of the oxidative stress variables revealed an increased level of SOD (U/mL) in subjects with schizophrenia versus control group. In addition, lipid damage measured as LOOHs µ (mol/L) and MDA was significantly higher in patients with schizophrenia in comparison to control subjects. There was a positive correlation between MDA µmol/L and PANSS P and a positive correlation between C-reactive protein (CRP) and the PANSS P scale. The elevated level of superoxide dismutase in patients with the first episode of schizophrenia can be explained by compensatory mechanisms to counteract oxidative stress. Malondialdehyde can be used as a simple biomarker of low-grade systemic inflammation associated with oxidative stress. A positive correlation between CRP and PANSS P scale and MDA and PANSS P scale may indicate a significant relationship between the development of low-grade inflammation and damage associated with oxidative stress in the development of the first symptoms of schizophrenia.

Fractalkine, sICAM-1 and Kynurenine Pathway in Restrictive Anorexia Nervosa-Exploratory Study.

The link between the kynurenine pathway and immunomodulatory molecules-fractalkine and soluble intercellular adhesion molecule-1 (sICAM-1)-in anorexia nervosa (AN) remains unknown. Fractalkine, sICAM-1, tryptophan (TRP), kynurenine (KYN), neuroprotective kynurenic acid (KYNA), neurotoxic 3-OH-kynurenine (3-OH-KYN), and the expression of mRNA for kynurenine aminotransferases (KAT1-3) were studied in 20 female patients with restrictive AN (mostly drug-free, all during first episode of the disease) and in 24 controls. In AN, serum fractalkine, but not sICAM-1, KYNA, KYN, TRP or 3-OH-KYN, was higher; ratios TRP/KYN, KYN/KYNA, KYN/3-OH-KYN and KYNA/3-OH-KYN were unaltered. The expression of the gene encoding KAT3, but not of genes encoding KAT1 and KAT2 (measured in blood mononuclear cells), was higher in patients with AN. In AN, fractalkine positively correlated with TRP, while sICAM-1 was negatively associated with 3-OH-KYN and positively linked with the ratio KYN/3-OH-KYN. Furthermore, TRP and fractalkine were negatively associated with the body mass index (BMI) in AN. Expression of KAT1, KAT2 and KAT3 did not correlate with fractalkine, sICAM-1 or BMI, either in AN or control. Increased fractalkine may be an independent factor associated with the restrictive type of AN. Excessive physical activity probably underlies increased expression of KAT3 observed among enrolled patients. Further, longitudinal studies on a larger cohort of patients should be aimed to clarify the contribution of fractalkine and KAT3 to the pathogenesis of AN.

Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease.

BACKGROUND: Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals. METHODS: The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I-III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn's disease (CD)] and in 50 control individuals. RESULTS: The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse-remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase-remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission. CONCLUSION: The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.

Imbalance of Controlled Death in Peripheral Blood Lymphocytes in Crohn's Disease and Ulcerative Colitis.

Background and objectives: Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Both conditions are associated with an exacerbated intestinal immune response to harmless stimuli, leading to upregulation of pro-inflammatory mediators. Materials and Methods: The subjects of the study were 55 patients with IBD. The control group consisted of 35 healthy subjects. The researched material consisted of peripheral blood lymphocytes collected from the subjects. Expression of the genes BAX, BCL2, CASP3 and CASP9 was assessed at the mRNA level in the peripheral blood lymphocytes of patients with ulcerative colitis and Crohn's disease relative to the healthy subjects. The expression of the genes was determined by rtPCR using TaqMan probes specific for these genes. Results: The group of patients diagnosed with CD had statistically significantly higher expression of the genes BAX (p = 0.012), BCL2 (p = 0.022), CASP3 (p = 0.003) and CASP9 (p = 0.029) than healthy subjects. Expression of BAX, BCL2, CASP3 and CASP9 in UC patients in the active phase of the disease was significantly lower than in patients in remission: BAX (p = 0.001), BCL2 (p = 0.038) and CASP9 (p = 0.007). In patients with UC, the BAX/BCL2 ratio was significantly correlated (r = 0.473) with the duration of the disease. In the group of CD patients treated biologically, a significantly lower BAX/BCL2 ratio was demonstrated than in patients that were not biologically treated. Conclusions: Our research has shown a simultaneous increase in the expression of the anti-apoptotic BCL2 gene and the proapoptotic BAX gene, which suggests the dysregulation of apoptosis mechanisms in IBD. Significantly higher expression of BAX and BCL2 in UC patients in remission as compared to CD may suggest differences in these diseases in terms of prognosis and treatment. Our results may suggest that an underlying imbalance in factors controlling apoptosis in peripheral blood lymphocytes may be the response of the immune system to inflammation of the intestinal mucosa. Modulation of apoptosis may become an important therapeutic mechanism in IBD.

Analysis of the expression of BAX, BCL2, BIRC6, CASP3, CASP9 apoptosis genes during the first episode of schizophrenia. / Analiza ekspresji genów apoptozy: BAX, BCL2, BIRC6, CASP3, CASP9 w pierwszym epizodzie schizofrenii.

OBJECTIVES: The aim of the study was the analysis of (1) the level of BAX,BCL2,BIRC6,CASP3, CASP9 apoptosis genes expression in schizophrenic patients and in the control group, and (2) the relationships between the genes expression level and the morphological and biochemical parameters, as well as the severity of psychopathological symptoms. METHODS: The study included 21 patients diagnosed with schizophrenia according to ICD-10 and 26 healthy subjects. The following parameters were assessed: genes expression in peripheral blood lymphocytes, laboratory parameters and severity of psychopathological symptoms (using the PANSS). RESULTS: The expression of the BCL2 gene and the CASP3 gene was significantly higher in schizophrenic patients compared to the controls. A significant positive correlation was found between the BAX gene expression level and neutrophil, lymphocyte and monocyte counts as well as the severity of negative symptoms (PANSS-N), between BCL2 and CASP9 genes expression and the monocyte count, and between the CASP3 gene expression and the lymphocyte count. CONCLUSIONS: (1) Significantly higher expression of BCL2 and CASP3 genes in schizophrenic patients compared to the controls proves the intensification of the apoptosis process, fitting in the theory of increased apoptosis in the pathophysiology of schizophrenia. (2) Significant correlations between the BAX gene expression and differential blood count parameters (leucocyte, neutrophil, lymphocyte, monocyte count) in the group of schizophrenic patients suggest a relationship with immune dysregulation and confirm the presence of apoptosis in peripheral blood lymphocytes. (3) The BAX gene expression may be indicative of the severity of negative symptoms in schizophrenia. (4) The analysis of the intercorrelation of studied genes expression indicates that BAX and CASP3 genes were the most active in the apoptosis process in the study group.

Correlations of Kynurenic Acid, 3-Hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with Clinical Symptoms During Acute Relapse of Schizophrenia.

Several lines of evidence suggest that up-regulation of immune response and alterations of kynurenine pathway function are involved in pathogenesis of schizophrenia. Correlations among clinical status (using PANNS, SANS and SAPS scales) and blood levels of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and levels of selected immunoactive molecules, soluble interleukin-2 receptor (sIL-2R), interferon-α (IFN-α) and IL-4 were analyzed in 51 chronic schizophrenia patients during acute relapse, after four weeks of therapy and at remission. KYNA levels were significantly lower in comparison with controls (N=45) throughout the study, whereas 3-HK did not differ from controls at admission and during therapy, but increased at remission. The KYNA/3-HK ratio and IL-4 levels, but not sIL-2R and IFN-α levels, were consistently decreased in schizophrenia patients at all analyzed time points. KYNA level and KYNA/3-HK ratio measured at admission correlated negatively with the duration of illness, whereas 3-HK level correlated negatively with the improvement of SANS score at discharge. sIL-2R level before treatment was positively linked with number of relapses. In the subgroup of patients with poor response to pharmacotherapy, treated with clozapine later on, initial KYNA level and the ratio KYNA/3-HK correlated negatively with number of relapses. Positive association of sIL-2R level with number of relapses was also evident in this subgroup. Furthermore, among these patients, starting IFN-α level was negatively linked with the improvement of total PANSS score at discharge. Presented here data support the concept of disturbed kynurenine pathway function in schizophrenia and suggest that assessment of KYNA and 3-HK levels during acute relapse might be useful in prediction of response to antipsychotic therapy. Deficit of peripheral KYNA and higher 3-HK levels could be associated with more severe symptoms of schizophrenia. Further studies with larger samples size are needed to validate our results.

[The kynurenic acid hypothesis - a new look at etiopathogenesis and treatment of schizophrenia]. / Koncepcja kynureninowa ­ nowe spojrzenie na etiopatogeneze i leczenie schizofrenii.

Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan formed in the brain and in the periphery, known to block ionotropic glutamate receptors and α7 nicotinic receptors, and to act as a ligand of G protein-coupled GPR35 receptors and human aryl hydrocarbon (AHR) receptors. KYNA seems to modulate a number of mechanisms involved in the pathogenesis of schizophrenia including dopaminergic transmission in mesolimbic and mesocortical areas or glutamatemediated neurotransmission. The kynurenine hypothesis of schizophrenia links the occurrence of positive and negative symptoms of schizophrenia and cognitive impairments characteristic for the disease with the disturbances of kynurenine pathway function. Available data suggest that antipsychotic drugs may restore balance among kynurenine pathway metabolites, and that co-administration of glycine with antipsychotics may reduce extrapyramidal symptoms in patients suffering from schizophrenia. Central level of KYNA may increase in the course of inflammation, which is consistent with the inflammatory hypothesis of schizophrenia. Alterations of immune response and disturbed functioning of kynurenine pathway may lead to disproportion between neuroprotective and neurotoxic mechanisms in the brain. Currently, intense research efforts are focused on the role of kynurenine pathway metabolites in pathogenesis of schizophrenia, their association with the response to antipsychotic treatment, and search for novel medications modulating the function of kynurenine pathway.

[New prospects for antipsychotic treatment - the role of the kynurenine pathway]. / Nowe perspektywy w leczeniu przeciwpsychotycznym - znaczenie szlaku kynureninowego.

The mechanism of action of antipsychotic drugs is mainly associated with changes in dopaminergic system. The application of antipsychotic agents simultaneously produces changes in concentrations of metabolites (e.g. kynurenic acid - KYNA, 3-hydroxykynurenine - 3-OHKYN, kynurenine - KYN) of the kynurenine pathway, the pathway engaged in glutamatergic transmission. The increase in KYNA levels in certain areas of the central nervous system results in inhibition of glutamatergic transmission. Pharmacologically induced elevation of KYNA levels produces effects similar to those observed after administering ketamine or phencyclidine (the noncompetitive NMDA receptor antagonist), concerning increased activity of mesolimbic dopamine neurons, as well as reduction in dopamine release from the prefrontal cortex. Recent research results confirm the predictive value of changes in concentrations of kynurenine pathway metabolites for assessment of effectiveness of antipsychotic treatment. Significant relationships were found 1) in schizophrenia between the reduction of psychopathological symptoms and variations in 3-OHKYN levels as well as changes in KYNA/3-OHKYN and KYN/KYNA ratios, 2) in mania between varying tryptophan concentrations and the reduction in manic symptoms achieved with antipsychotic treatment. The research as well presented the possibilities of kynurenine pathway modifications, raising high hopes for their future application as target points for the action of novel antipsychotic agents.

[Changes of sense of coherence (SOC) after psychotherapy in neurotic patients]. / Zmiany poczucia koherencji (SOC) po psychoterapii u pacjentów z zaburzeniami nerwicowymi.

UNLABELLED: Sense of coherence (SOC) is the central construct of the salutary model of health. Sense of coherence comprises comprehensibility, manageability and meaningfulness. AIM: The aim of the study was to check if the sense of coherence can change after psychotherapy in neurotic patients, if the value of the changes depends on the level of sense of coherence and if the obtained changes are stable. METHOD: 101 patients (32 males, 69 females, aged between 17 and 48 years) with neurotic disorders defined according to ICD-10 criteria were the subject of the study. This group of patients were hospitalized in the Neurotic Ward of the Psychiatry Department in Lublin. They took part in a 10-week psychotherapeutic programme. In the study, the authorized Polish adaptation of the Orientation to Life Questionnaire (SOC-29) by Antonovsky was used to measure the sense of coherence. Patients were examined prior to and on completion of the treatment programme. In the next stage of the study patients filled in the SOC-29 Questionnaire after six months. Dependent sample t-test was used in data analysis. RESULTS: Significant favourable changes were found in patients with a low SOC level. The increase of SOC was observed after a 10-week treatment. The increase was stable in examination after six months. Changes in sense of coherence in the group with high SOC level were not observed. The results suggest that the therapy can be more effective in patients with a low SOC level.