Repositioning of the antipsychotic drug TFP for sepsis treatment

Abstract

Sepsis is a disease responsible for the death of almost all critical patients. Once infected by virus or bacteria, patients can die due to systemic inflammation within a short period of time. Cytokine storm plays an essential role in causing organ dysfunction and septic shock. Thus, inhibition of cytokine secretion is considered very important in sepsis therapy. In this study, we found that TFP, an antipsychotic drug mainly used to treat schizophrenia by suppressing dopamine secretion, inhibited cytokine release from activated immune cells both in vitro and in vivo. Trifluoperazine (TFP) decreased the levels of pro-inflammatory cytokines without altering their transcription level. In LPS-induced endotoxemia and cecal content injection (CCI) models, TFP intraperitoneal administration improved survival rate. Thus, TFP was considered to inhibit the secretion of proteins through a mechanism similar to that of W7, a calmodulin inhibitor. Finally, we confirmed that TFP treatment relieved organ damage by estimating the concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and blood urea nitrogen (BUN) in the serum. Our findings were regarded as a new discovery of the function of TFP in treating sepsis patients. Key messages • TFP inhibits LPS-induced activation of DCs by suppressing pro-inflammatory cytokine. • Treatment of TFP increases survival of LPS-induced endotoxemia and CCI sepsis models. • TFP exerted a protective effect against tissue or organ damage in animal models. Electronic supplementary material The online version of this article (10.1007/s00109-019-01762-4) contains supplementary material, which is available to authorized users.

Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

“…In TFP’s case, it had been shown to modulated immune system. It suppressed cytokine release from activated immune cells both in vitro and in vivo and improved survival rate in sepsis models (Park et al, 2019). Another study found that TFP combated respiratory and gastrointestinal bacterial pathogens probably through affecting the host immune system (Andersson et al, 2016).…”

“…TFP is known to be a calmodulin inhibitor. One of other proposed modes of effects of TFP is its ability of binding to a well-known Ca 2+ binding protein, calmodulin (CaM) (Kang et al, 2017; Park et al, 2019). TFP is also shown to promote FOXO3 nuclear localization and activation to suppress breast cancer (Park et al, 2016).…”

“…It reduced lymphocyte proliferation both in vitro and in vivo and might cause immunosuppression (Roudebush et al, 1991). During sepsis, it reduced inflammatory response by inhibiting cytokine release in LPS-stimulated macrophages and dendritic cells (Park et al, 2019). The above information indicated that immune system might be evolved in TFP’s anticancer effects.…”

The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice

“…Apparent normalization of some cytokine levels following treatment of schizophrenia with antipsychotic drugs as well as in vitro demonstrations of their ability to impact pro-and anti-inflammatory cytokines [29][30][31][32] has led to speculation and analysis that immunomodulation is a previously unrecognized component of their therapeutic effect for patients experiencing psychosis [33]. The notion of therapeutically relevant immunomodulation has been applied to lethal inflammatory conditions such as bacterial sepsis, wherein the typical antipsychotic drug trifluoperazine showed an improved survival and reduced organ damage in a preclinical model [34]. This reciprocal potential for drug repurposing is reflective of the bi-directional interactions between the immune and nervous systems, notable here for the demonstrated involvement of dopaminergic and serotonergic signaling in both processes.…”

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

“…Adding another level of complexity in the interaction between the dopaminergic and immune system, some studies have shown that some drugs targeting dopaminergic system might regulate inflammation. According to the critical role of dopamine in the regulation of sepsis (Torres-Rosas et al, 2014), it has recently been shown that the antipsychotic drug trifluoperazine (TFP), which suppress dopamine secretion, exerted a strong regulation of proinflammatory cytokines and increased the survival rate in animal models of sepsis (Park et al, 2019). Another example illustrating the role of antipsychotic drugs is the study of the effect of paliperidone in neuroinflammation.…”