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

Cells

João Quevedo¹  Fabricia Petronilho²  Danielle Macêdo³  Giselli Scaini⁴  Tejaswini Doifode⁴  GabrielaD. Colpo⁴  AntônioL. Teixeira⁴  OmarF. Pinjari⁴  Tatiana Barichello⁴  VijayasreeV. Giridharan⁴ 

[1] National Institute for Translational Medicine (INCT-TM, CNPq), 14000-000 Ribeirão Preto, SP, Brazil;Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of South Santa Catarina, Tubarão, 88700-000 Santa Catarina, Brazil;Neuropsychopharmacology Laboratory, Drug Research, and Development Center, Faculty of Medicine, Universidade Federal do Ceará, 60020-181 Fortaleza CE, Brazil;Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77054 USA;

关键词: microglia;    poly (i:c);    inflammation;    nlrp3;    cytokines;    schizophrenia;   

DOI  :  10.3390/cells9030577

来源: DOAJ

【 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 μM, respectively), on the production of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, IL-18, INF-γ, and TNF-α 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-1α, IL-1β, IL-2, and IL-17. Risperidone and haloperidol both reduced the levels of IL-1α, IL-1β, IL-2, and IL-17, and increased the levels of IL-6, IL-10, INF-γ, and TNF-α. 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-1α, IL-1β, 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.

【 授权许可】

Unknown