Clozapine Prevents Poly (I:C) Induced Inflammation by Modulating NLRP3 Pathway in Microglial Cells

被引：43

作者：

Giridharan, Vijayasree V. ^{[1
]}

Scaini, Giselli ^{[1
]}

Colpo, Gabriela D. ^{[1
]}

Doifode, Tejaswini ^{[1
]}

Pinjari, Omar F. ^{[1
]}

Teixeira, Antonio L. ^{[1
]}

Petronilho, Fabricia ^{[2
]}

Macedo, Danielle ^{[3
,4
]}

Quevedo, Joao ^{[1
,5
,6
,7
]}

Barichello, Tatiana ^{[1
,8
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Faillace Dept Psychiat & Behav Sci, Translat Psychiat Program,UTHlth, Houston, TX 77054 USA

[2] Univ South Santa Catarina, Hlth Sci Unit, Lab Neurobiol Inflammatory & Metab Proc, Grad Program Hlth Sci, BR-88700000 Tubarao, SC, Brazil

[3] Univ Fed Ceara, Fac Med, Drug Res & Dev Ctr, Neuropsychopharmacol Lab, Fortaleza, Ceara, Brazil

[4] CNPq, Natl Inst Translat Med INCT TM, BR-14000000 Ribeirao Preto, SP, Brazil

[5] Univ Southern Santa Catarina UNESC, Translat Psychiat Lab, Grad Program Hlth Sci, BR-88800000 Criciuma, SC, Brazil

[6] Univ Texas MD Anderson Canc Ctr, Neurosci Grad Program, UTHlth, Grad Sch Biomed Sci, Houston, TX 77030 USA

[7] Univ Texas Hlth Sci Ctr Houston, Ctr Excellence Mood Disorders, McGovern Med Sch, Faillace Dept Psychiat & Behav Sci,UTHlth, Houston, TX 77054 USA

[8] Univ Southern Santa Catarina, Lab Expt Pathophysiol, Grad Program Hlth Sci, BR-88800000 Criciuma, SC, Brazil

来源：

CELLS | 2020年 / 9卷 / 03期

关键词：

microglia; poly (I:C); inflammation; NLRP3; cytokines; schizophrenia; SCHIZOPHRENIA; ACTIVATION; ANTIPSYCHOTICS; INHIBITOR; CYTOKINES; UPDATE; SYSTEM; MATTER; PYRIN; GRAY;

D O I：

10.3390/cells9030577

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Schizophrenia is a complex psychiatric disorder that exhibits an interconnection between the immune system and the brain. Experimental and clinical studies have suggested the presence of neuroinflammation in schizophrenia. In the present study, the effect of antipsychotic drugs, including clozapine, risperidone, and haloperidol (10, 20 and 20 mu M, respectively), on the production of IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-gamma, and TNF-alpha was investigated in the unstimulated and polyriboinosinic-polyribocytidilic acid [poly (I:C)]-stimulated primary microglial cell cultures. In the unstimulated cultures, clozapine, risperidone, and haloperidol did not influence the cytokine levels. Nevertheless, in cell cultures under strong inflammatory activation by poly (I:C), clozapine reduced the levels of IL-1 alpha, IL-1 beta, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1 alpha, IL-1 beta, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-gamma, and TNF-alpha. Based on the results that were obtained with the antipsychotic drugs and observing that clozapine presented with a more significant anti-inflammatory effect, clozapine was selected for the subsequent experiments. We compared the profile of cytokine suppression obtained with the use of NLRP3 inflammasome inhibitor, CRID3 to that obtained with clozapine, to test our hypothesis that clozapine inhibits the NLRP3 inflammasome. Clozapine and CRID3 both reduced the IL-1 alpha, IL-1 beta, IL-2, and IL-17 levels. Clozapine reduced the level of poly (I:C)-activated NLRP3 expression by 57%, which was higher than the reduction thay was seen with CRID3 treatment (45%). These results suggest that clozapine might exhibit anti-inflammatory effects by inhibiting NLRP3 inflammasome and this activity is not typical with the use of other antipsychotic drugs under the conditions of strong microglial activation.

引用

页数：14

共 49 条

[1] Effects of Antipsychotics on the Inflammatory Response System of Patients with Schizophrenia in Peripheral Blood Mononuclear Cell Cultures [J].