The role of sulpiride in attenuating the cardiac, renal, and immune disruptions in rats receiving clozapine: mRNA expression pattern of the genes encoding Kim-1, TIMP-1, and CYP isoforms

Mohammed, Amira; Khalil, Samah R.; Mahmoud, Fagr A.; Elmowalid, Gamal A.; Ali, Haytham; El‐Serehy, Hamed A.; Abdel-Daim, Mohamed M.

doi:10.1007/s11356-020-08914-x

Cited by 4 publications

(6 citation statements)

References 44 publications

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“…Several groups have reported clozapine-mediated hepatic ( Jia et al , 2014 ; Zlatkovic et al , 2014 ), cardiac ( Abdel-Wahab and Metwally, 2015 ; Mohammed et al , 2020 ; Nikolic-Kokic et al , 2018 ; Wang et al , 2008 ), splenic ( Abdelrahman et al , 2014 ; Mohammed et al , 2020 ), and other ( Lobach and Uetrecht, 2014b ; Ng et al , 2014 ; Wasti et al , 2006 ) immune changes but, aside from our group, these effects have been reported following several weeks, not hours, of clozapine administration (reviewed in Sernoskie et al [2021 ]). The differences in inflammatory mediator changes observed in the spleen and bone marrow in the present study not only underscore the complexity of the immune response to clozapine, but the observed increases in IL-1β and other proinflammatory mediators support further investigation of organ-specific inflammasome activation in this response in vivo .…”

Section: Discussionmentioning

confidence: 62%

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Sernoskie

Lobach

Kato

et al. 2021

Toxicological Sciences

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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 non-differentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1β 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-1β, 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-1β 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 idiosyncratic drug-induced agranulocytosis, enabling safer, more frequent use of clozapine in patients.

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Section: Discussionmentioning

confidence: 62%

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Sernoskie

Lobach

Kato

et al. 2021

Toxicological Sciences

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“…Clozapine-altered chemistry parameters (e.g., ALT, BUN) may be relevant for other adverse effects including liver injury (Wu Chou et al, 2014;Oates et al, 2018;Gunther and Dopheide, 2023) and acute interstitial nephritis (Davis and Kelly, 2019;McLoughlin et al, 2022;Vantipalli et al, 2022), and these IDRs may share early mechanisms. Indeed, with repeat clozapine dosing, increased hepatic covalent binding (Gardner et al, 2005;Ip and Uetrecht, 2008) and inflammatory changes in the liver (Jia et al, 2014;Zlatkovic et al, 2014;Sernoskie et al, 2023) and the kidney (Mohammed et al, 2020) have been observed. Studies investigating cell damage in these organs may elucidate additional immune-activating events.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis

Sernoskie,

Bonneil,

Thibault

et al. 2024

J Pharmacol Exp Ther

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Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDRassociated drugs. To explore the hypothesis that EVs are also a source of DAMPs in the induction of the immune response preceding drug-induced agranulocytosis, the proteome and immunogenicity of clozapine-(agranulocytosis-associated drug) and olanzapine-(nonagranulocytosis-associated drug) exposed EVs were compared in two preclinical models: THP-1 macrophages and Sprague Dawley rats. Compared to olanzapine, clozapine induced a greater increase in the concentration of EVs enriched from both cell culture media and rat serum.Moreover, treatment of drug-naïve THP-1 cells with clozapine-exposed EVs induced an inflammasome-dependent response, supporting a potential role for EVs in immune activation.Proteomic and bioinformatic analyses demonstrated an increased number of differentially expressed proteins with clozapine that were enriched in pathways related to inflammation, myeloid cell chemotaxis, wounding, transforming growth factor (TGF)-β signaling, and negative regulation of stimuli response. These data indicate that, although clozapine and olanzapine exposure both alter the protein cargo of EVs, clozapine-exposed EVs carry mediators that exhibit significantly greater immunogenicity. Ultimately, this supports the working hypothesis that drugs associated with a risk of IDRs induce cell stress, release of proinflammatory mediators, and early immune activation that precedes severe reaction onset. Further studies characterizing EVs may elucidate biomarkers that predict IDR risk during development of drug candidates.

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“…The effects of clozapine on various other organs, including the brain, heart, and kidney, have been investigated using several rodent models. In studies characterizing the effects of clozapine in the absence of induced injury or disease, decreased splenic white pulp was observed in both female mice and male rats (Abdelrahman et al, 2014;Mohammed et al, 2020), and both ovarian and kidney injury were reported in rats (Khalaf et al, 2019;Mohammed et al, 2020). Moreover, significant cardiac inflammation and morphologic aberrations were observed during the first few weeks of treatment (Wang et al, 2008;Nikoli c-Koki c et al, 2018;Mohammed et al, 2020).…”

Section: Clozapinementioning

confidence: 99%

“…In studies characterizing the effects of clozapine in the absence of induced injury or disease, decreased splenic white pulp was observed in both female mice and male rats (Abdelrahman et al, 2014;Mohammed et al, 2020), and both ovarian and kidney injury were reported in rats (Khalaf et al, 2019;Mohammed et al, 2020). Moreover, significant cardiac inflammation and morphologic aberrations were observed during the first few weeks of treatment (Wang et al, 2008;Nikoli c-Koki c et al, 2018;Mohammed et al, 2020). This parallels what is observed clinically because, in addition to severe IDRs, clozapine has been associated with an increased risk of myocarditis in patients, which can present with fever, eosinophilia, and increased troponin levels, often during weeks 2 and 3 of treatment (Kilian et al, 1999;Ronaldson et al, 2010;Curto et al, 2015).…”

Section: Clozapinementioning

confidence: 99%

“…Contrarily, few studies characterized the inflammatory mediator changes caused by clozapine alone. Of these studies, most demonstrated an increase in proinflammatory mediators in either rats or mice, including TNF-a, CXCL2, and heat shock protein 75 (Wang et al, 2008;Lobach and Uetrecht, 2014a;Kedracka-Krok et al, 2016;Mohammed et al, 2020). Few studies have reported alterations in bioactive lipids in response to the drugs reviewed; however, dysregulated arachidonic acid signaling was also noted with clozapine treatment (Kim et al, 2012;Modi et al, 2013).…”

Section: Clozapinementioning

confidence: 99%

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The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

2021

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The role of sulpiride in attenuating the cardiac, renal, and immune disruptions in rats receiving clozapine: mRNA expression pattern of the genes encoding Kim-1, TIMP-1, and CYP isoforms

Cited by 4 publications

References 44 publications

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

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