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Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis.
Sernoskie, Samantha Christine; Lobach, Alexandra R; Kato, Ryuji; Jee, Alison; Weston, Joseph Kyle; Uetrecht, Jack.
Afiliación
  • Sernoskie SC; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Lobach AR; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Kato R; Department of Cardiovascular Pharmacotherapy and Toxicology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka 569-1094, Japan.
  • Jee A; Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Weston JK; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
  • Uetrecht J; Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
Toxicol Sci ; 186(1): 70-82, 2022 02 28.
Article en En | MEDLINE | ID: mdl-34935985
Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and nondifferentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1ß release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1ß, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1ß production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of IDIAG, enabling safer, more frequent use of clozapine in patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Clozapina / Agranulocitosis Límite: Animals / Humans Idioma: En Revista: Toxicol Sci Asunto de la revista: TOXICOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Clozapina / Agranulocitosis Límite: Animals / Humans Idioma: En Revista: Toxicol Sci Asunto de la revista: TOXICOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos