The atypical antipsychotic clozapine selectively inhibits interleukin 8 (IL-8)-induced neutrophil chemotaxis

Capannolo, Marta; Fasciani, Irene; Romeo, Stefania; Aloisi, Gabriella; Rossi, Mario; Bellio, Pierangelo; Celenza, Giuseppe; Cinque, Benedetta; Cifone, Maria Grazia; Scarselli, Marco; Maggio, Roberto

doi:10.1016/j.euroneuro.2014.12.002

Cited by 16 publications

(10 citation statements)

References 46 publications

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“…Our results reveal that the long-term administration of clozapine did not increase the levels of proinflammatory chemokines. Only a significant decrease in MCP-3 was found in the mice treated with clozapine, which is compatible with a previous in-vitro cell culture study which found that clozapine reduced PMN chemotaxis [18] . Our results suggest that this mechanism of clozapine-associated derangements of glucose metabolism is multifactorial.…”

Section: Discussionsupporting

confidence: 91%

GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

Hsu

2016

Toxicology Reports

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Background and aimsThe aim of this study was to investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), exenatide, on clozapine-associated glucose dysregulation in mice.Materials and methodsWe randomly separated B6 male mice into four groups (A to D). Mice in groups C and D received a daily oral dose of 13.5 mg/kg body weight of clozapine for 4 months. Mice in groups B and D received 1 μg of exenatide daily. The body weight and blood glucose before and 2 h after clozapine treatment were measured twice a week. Intraperitoneal glucose tolerance test (IPGTT) scores and the amount of daily food intake were recorded. The pancreases of the mice were removed for insulin content (PIC) measurement and histological examination after sacrifice.ResultsThe mean non-fasting blood glucose levels were not different, and the mean changes in blood glucose 2 h after oral clozapine were 0 ± 4, −40 ± 2, 25 ± 3, and −39 ± 2, in groups A to D, respectively. There was no significant difference in daily calorie intake or area under the curve of IPGTT among the four groups. At sacrifice, the PIC of mice treated with clozapine was significantly lower than that of the control mice, however the PIC was completely restored in the mice treated with exenatide. Histological examination of the pancreas revealed that exenatide treatment reversed the clozapine-induced apoptosis of islet cells.ConclusionOur results provide preclinical evidence of a pharmaceutical role of GLP-1RA in managing glucose dysregulation in schizophrenic patients under long-term atypical antipsychotic treatments.

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Section: Discussionsupporting

confidence: 91%

GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

Hsu

2016

Toxicology Reports

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“…[41][42][43][44] In fact, both in vitro and in vivo studies confirmed the immunomodulatory actions of clozapine. [45][46][47][48][49] These effects of clozapine on the immune system may account for its efficacy in the treatment of schizophrenia in accordance with an immunological hypothesis of disorder etiology, 50,51 but also for some adverse effects (i.e. eosinophilia, benign hyperthermia, cardiovascular and hematological adverse effects etc.).…”

Section: Clozapine Mechanism Of Action and Relationships With Adversementioning

confidence: 99%

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

Berardis¹,

Rapini²,

Olivieri³

et al. 2018

Therapeutic Advances in Drug Safety

156

125

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Clozapine, a dibenzodiazepine developed in 1961, is a multireceptorial atypical antipsychotic approved for the treatment of resistant schizophrenia. Since its introduction, it has remained the drug of choice in treatment-resistant schizophrenia, despite a wide range of adverse effects, as it is a very effective drug in everyday clinical practice. However, clozapine is not considered as a top-of-the-line treatment because it may often be difficult for some patients to tolerate as some adverse effects can be particularly bothersome (i.e. sedation, weight gain, sialorrhea etc.) and it has some other potentially dangerous and life-threatening side effects (i.e. myocarditis, seizures, agranulocytosis or granulocytopenia, gastrointestinal hypomotility etc.). As poor treatment adherence in patients with resistant schizophrenia may increase the risk of a psychotic relapse, which may further lead to impaired social and cognitive functioning, psychiatric hospitalizations and increased treatment costs, clozapine adverse effects are a common reason for discontinuing this medication. Therefore, every effort should be made to monitor and minimize these adverse effects in order to improve their early detection and management. The aim of this paper is to briefly summarize and provide an update on major clozapine adverse effects, especially focusing on those that are severe and potentially life threatening, even if most of the latter are relatively uncommon.

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“…Given that MRPs also pump AA-derived eicosanoids including LTB 4 and PGE 2 out to the extracellular matrix (Capannolo et al 2015;Chen et al 2017;Rius et al 2008), the levels of eicosanoids could be considered activity indicators of MRPs. We used UPLC-MS/MS to analyze the AA metabolome in the supernatants of cells.…”

Section: Resultsmentioning

confidence: 99%

The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer

Zhang

Lei

Wang

et al. 2020

Mol Med

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Background: Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinumresistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. Methods: Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the cotranscription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. Results: SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AAmetabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. Conclusion: Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.

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The atypical antipsychotic clozapine selectively inhibits interleukin 8 (IL-8)-induced neutrophil chemotaxis

Cited by 16 publications

References 46 publications

GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice

Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine

The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer

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