Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

Abstract

BackgroundMetabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined.Methodology/Principal FindingsCultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 µM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line.Conclusions/SignificanceClozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.

Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

“…Finally, in this study, we assessed the short-term effect of clozapine (over 2 to 3 days), but not the long-term effect. Although the dose of clozapine that we used was rational and has been implemented in many studies [22,42,43], we also demonstrated that even at a lower concentration, clozapine continued to impair NSCLC cell growth during treatment for a longer period. Not only is this finding consistent with the clinical observation that patients with schizophrenia require prolonged antipsychotic administration [24], but the dose that we used for long-term treatment was also closer to the actual dose used in the clinic [44,45].…”

Antibiotics-Induced Obesity: A Mitochondrial Perspective

“…Streptomycin administration linked with G1555A mutation results in ototoxicity and deafness [89]. Further, clozapine treatment may give rise to increased production of pro-inflammatory cytokines involved in inflammation, which in turn is associated with alterations in mitochondrial function and obesity [95] (Table 1, 2). The antidiabetic drug metformin was found to inhibit OXPHOS by directly targeting the ETC, thus acting as a mitochondrial inhibitor as well as inducing lactic acidosis [96,97].…”

Antipsychotics-induced metabolic alterations: Focus on adipose tissue and molecular mechanisms

“…Although there is insufficient evidence for the association between elevated inflammatory markers and the etiopathology of schizophrenia (Manu et al, 2014), proinflammatory mediators and inflammation are well known to negatively affect the metabolism of glucose and to induce insulin resistance and T2DM (Contreras-Shannon et al, 2013). Interestingly, atypical antipsychotics induce the transcription factor nuclear factor-κB (NF-κB) and NF-κB target genes such as the proinflammatory cytokines TNF-α, IL-1β, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in human adipocytes (Sarvari et al, 2014).…”

“…Interestingly, atypical antipsychotics induce the transcription factor nuclear factor-κB (NF-κB) and NF-κB target genes such as the proinflammatory cytokines TNF-α, IL-1β, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in human adipocytes (Sarvari et al, 2014). In addition, atypical antipsychotics increase the secretion of proinflammatory cytokines by rat adipocytes (Contreras-Shannon et al, 2013), and the secretion of both IL-8 and MCP-1 by human adipocytes (Sarvari et al, 2014). Elevated levels of MCP-1 can potentially induce monocytes/macrophages recruitment into the adipose tissue, which can in turn increase even more the secretion of inflammatory mediators such as TNF-α.…”

“…Elevated levels of MCP-1 can potentially induce monocytes/macrophages recruitment into the adipose tissue, which can in turn increase even more the secretion of inflammatory mediators such as TNF-α. Interestingly, clozapine treatment has been demonstrated to alter the secretion of proinflammatory cytokines by adipocytes (Contreras-Shannon et al, 2013). Moreover, olanzapine-treated rats show a greater accumulation of adipose tissue with extensive macrophage infiltration and TNF-α expression, and a higher plasma concentration of TNF-α and IL-1β (Victoriano et al, 2010).…”