Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells
Schizophrenia (SCZ) is a chronic neurodevelopmental psychotic disorder. The immune system and neuroinflammation seem to play a central role in the pathophysiology of SCZ. Clozapine is an effective atypical antipsychotic used for treatment-resistant SCZ. Life-threatening side effects, such as myocard...
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MDPI AG
2022-12-01
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| Series: | Brain Sciences |
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| author | Yael Yuhas Shai Ashkenazi Eva Berent Abraham Weizman |
| author_facet | Yael Yuhas Shai Ashkenazi Eva Berent Abraham Weizman |
| author_sort | Yael Yuhas |
| collection | DOAJ |
| description | Schizophrenia (SCZ) is a chronic neurodevelopmental psychotic disorder. The immune system and neuroinflammation seem to play a central role in the pathophysiology of SCZ. Clozapine is an effective atypical antipsychotic used for treatment-resistant SCZ. Life-threatening side effects, such as myocarditis, limit its use. We investigated the immunomodulatory effects of clozapine in an astroglial model of neuroinflammation. We thus assessed the effect of clozapine on the production of inflammatory mediators in human-derived astroglial (A172) cells, stimulated with a cytokine mix (TNFα, IL-1β, IFNγ). RT-PCR and ELISA analyses demonstrated that clozapine suppressed gene expression and production of TNFα, IL-1β and IL-8 and increased COX2 mRNA 24 h after stimulation. Clozapine inhibited Akt phosphorylation induced by the cytokine mix at 10 min and 40 min, as assessed by Western blot analysis with anti-pT308Akt antibody. Pretreatment with the Akt inhibitor MK-2206 increased COX2 gene expression in cytokine-stimulated cells, suggesting that Akt inhibition may be involved in COX2 gene expression upregulation. Clozapine may possess dual beneficial effects: inhibiting astroglial production of proinflammatory cytokines, thus attenuating neuroinflammation, and upregulating COX2 expression that may be relevant to improvement of neural functioning while accounting for some of its detrimental effects. Patients with TRS and neuroinflammatory markers may benefit particularly from clozapine treatment. |
| first_indexed | 2024-03-09T17:15:17Z |
| format | Article |
| id | doaj.art-7746039abcda48a9bfceeadc7df44901 |
| institution | Directory Open Access Journal |
| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-09T17:15:17Z |
| publishDate | 2022-12-01 |
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| record_format | Article |
| series | Brain Sciences |
| spelling | doaj.art-7746039abcda48a9bfceeadc7df449012023-11-24T13:40:15ZengMDPI AGBrain Sciences2076-34252022-12-011212170310.3390/brainsci12121703Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial CellsYael Yuhas0Shai Ashkenazi1Eva Berent2Abraham Weizman3Laboratory of Pediatric Infectious Diseases, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva 4941492, IsraelLaboratory of Pediatric Infectious Diseases, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva 4941492, IsraelLaboratory of Pediatric Infectious Diseases, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petach Tikva 4941492, IsraelLaboratory of Molecular and Biological Psychiatry, Felsenstein Medical Research Center, Petach Tikva 4941492, IsraelSchizophrenia (SCZ) is a chronic neurodevelopmental psychotic disorder. The immune system and neuroinflammation seem to play a central role in the pathophysiology of SCZ. Clozapine is an effective atypical antipsychotic used for treatment-resistant SCZ. Life-threatening side effects, such as myocarditis, limit its use. We investigated the immunomodulatory effects of clozapine in an astroglial model of neuroinflammation. We thus assessed the effect of clozapine on the production of inflammatory mediators in human-derived astroglial (A172) cells, stimulated with a cytokine mix (TNFα, IL-1β, IFNγ). RT-PCR and ELISA analyses demonstrated that clozapine suppressed gene expression and production of TNFα, IL-1β and IL-8 and increased COX2 mRNA 24 h after stimulation. Clozapine inhibited Akt phosphorylation induced by the cytokine mix at 10 min and 40 min, as assessed by Western blot analysis with anti-pT308Akt antibody. Pretreatment with the Akt inhibitor MK-2206 increased COX2 gene expression in cytokine-stimulated cells, suggesting that Akt inhibition may be involved in COX2 gene expression upregulation. Clozapine may possess dual beneficial effects: inhibiting astroglial production of proinflammatory cytokines, thus attenuating neuroinflammation, and upregulating COX2 expression that may be relevant to improvement of neural functioning while accounting for some of its detrimental effects. Patients with TRS and neuroinflammatory markers may benefit particularly from clozapine treatment.https://www.mdpi.com/2076-3425/12/12/1703schizophrenianeuroinflammationclozapineimmune systemproinflammatory cytokinesTNFα |
| spellingShingle | Yael Yuhas Shai Ashkenazi Eva Berent Abraham Weizman Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells Brain Sciences schizophrenia neuroinflammation clozapine immune system proinflammatory cytokines TNFα |
| title | Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells |
| title_full | Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells |
| title_fullStr | Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells |
| title_full_unstemmed | Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells |
| title_short | Clozapine Suppresses the Gene Expression and the Production of Cytokines and Up-Regulates Cyclooxygenase 2 mRNA in Human Astroglial Cells |
| title_sort | clozapine suppresses the gene expression and the production of cytokines and up regulates cyclooxygenase 2 mrna in human astroglial cells |
| topic | schizophrenia neuroinflammation clozapine immune system proinflammatory cytokines TNFα |
| url | https://www.mdpi.com/2076-3425/12/12/1703 |
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