| 1 | Transl Psychiatry 2011 -1 1: e36 |
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| PMID | 22832610 |
| Title | Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. |
| Abstract | Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TLRs) are pattern-recognition molecules that initiate inflammation. Our objective was to investigate the peripheral TLR activity in psychosis. Forty schizophrenia patients, twenty bipolar patients and forty healthy controls (HC) were recruited. Donated whole blood was cultured with TLR agonists for 24?h. Cell supernatants were analysed using a multiplex enzyme-linked immunosorbent assay approach to measure IL-1?, IL-6, IL-8 and tumour necrosis factor-? (TNF?). Plasma was analysed for cytokines, cortisol and acute phase proteins. Here, we show that selective TLR agonist-induced cytokine (IL-1?, IL-6, IL-8 and TNF?) release is enhanced in stimulated whole blood from schizophrenia and bipolar patients compared with HC. An exaggerated release of IL-1?, IL-6 and TNF? following treatment with the TLR2 agonist HKLM was detected in both disorders compared with controls. Enhanced TLR4-induced increases in IL-1? for both disorders coupled with TNF? increases for bipolar patients were observed. TLR8-induced increases in IL-1? for both disorders as well as IL-6 and TNF? increases for bipolar patients were detected. TLR9-induced increases in IL-8 for schizophrenia patients were also observed. No differences in TLR1, TLR3, TLR5, TLR6 or TLR7 activity were detected. Plasma levels of IL-6 were significantly elevated in bipolar patients while TNF? levels were significantly elevated in schizophrenia patients compared with controls. Plasma acute phase proteins were significantly elevated in bipolar patients. These data demonstrate that specific alterations in TLR agonist-mediated cytokine release contribute to the evidence of immune dysfunction in psychotic disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Gene 2013 Sep 526: 182-6 |
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| PMID | 23644137 |
| Title | Association between genetic polymorphisms of Toll-like receptor 2 (TLR2) and schizophrenia in the Korean population. |
| Abstract | Immunological dysregulation has been suggested to be involved in the pathogenesis of schizophrenia. Accumulating evidences further implicate that activated inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Toll-like receptor 2 (TLR2) plays an important role in innate immunity by sensing a variety of pathogens and inducing an acquired immunity. In the present study, we investigated whether the coding region of single nucleotide polymorphisms (SNPs) of the TLR2 gene was associated with schizophrenia as well as with clinical symptoms in schizophrenia patients. The study population consisted of 286 Korean schizophrenia patients and 305 Korean control subjects. The assessment of the Scale for the Assessment of Negative Symptoms was used to evaluate the negative symptoms of schizophrenia; the operational criteria checklist was used to measure general psychopathology. We selected two cSNPs [rs3804099 (Asn199Asn) and rs3804100 (Ser450Ser)] considering their heterozygosity and minor allele frequency. SNP genotyping was conducted using direct sequencing. We did not find any significant associations between SNPs and schizophrenia in the genotype and allelic frequencies. On the other hand, in the analysis of cognitive symptoms, rs3804099 showed significant differences in schizophrenia patients with poor concentration in the dominant model (TC/CC vs. TT, p=0.0099). Also, rs3804100 showed a significant association with poor concentration in the co-dominant (TC vs. TT, p=0.014) and the dominant models (TC/CC vs. TT, p=0.0035). We obtained no significant support for the association of the TLR2 gene with susceptibility to schizophrenia in the Korean population. However, our results provide possibility that C allele of rs3804099 and rs3804100 may be associated with poor concentration in schizophrenia patients. Further studies with larger samples are required to confirm our results. |
| SCZ Keywords | schizophrenia |
| 3 | Korean J. Physiol. Pharmacol. 2015 Jul 19: 365-72 |
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| PMID | 26170741 |
| Title | Immunotoxicological Effects of Aripiprazole: In vivo and In vitro Studies. |
| Abstract | Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor (NF)-?B, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages. |
| SCZ Keywords | schizophrenia |