Inhibitory Effects of Trifluoperazine on Peripheral Proinflammatory Cytokine Expression and Hypothalamic Microglia Activation in Obese Mice Induced by Chronic Feeding With High-Fat-Diet

Abstract

Microglia and astrocytes are the glial cells of the central nervous system (CNS) to support neurodevelopment and neuronal function. Yet, their activation in association with CNS inflammation is involved in the initiation and progression of neurological disorders. Mild inflammation in the periphery and glial activation called as gliosis in the hypothalamic region, arcuate nucleus (ARC), are generally observed in obese individuals and animal models. Thus, reduction in peripheral and central inflammation is considered as a strategy to lessen the abnormality of obesity-associated metabolic indices. In this study, we reported that acute peripheral challenge by inflammagen lipopolysaccharide (LPS) upregulated the expression of hypothalamic dopamine type 2 receptor (D2R) mRNA, and chronic feeding by high-fat-diet (HFD) significantly caused increased levels of D2R in the ARC. The in vitro and in vivo studies indicated that an FDA-approved antipsychotic drug named trifluoperazine (TFP), a D2R inhibitor was able to suppress LPS-stimulated activation of microglia and effectively inhibited LPS-induced peripheral inflammation, as well as hypothalamic inflammation. Further findings showed daily peripheral administration intraperitoneally (i.p.) by TFP for 4 weeks was able to reduce the levels of plasma tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in accompany with lower levels of plasma glucose and insulin in obese mice receiving HFD for 16 weeks when compared those in obese mice without TFP treatment. In parallel, the activation of microglia and astrocytes in the ARC was also inhibited by peripheral administration by TFP. According to our results, TFP has the ability to suppress HFD-induced ARC gliosis and inflammation in the hypothalamus.

Psilocin suppresses methamphetamine‐induced hyperlocomotion and acquisition of conditioned place preference via D2R‐mediated ERK signaling

“…Moreover, trifluoperazine blocks postsynaptic D2Rs in midbrain limbic and cortical projections 39 . Reports have demonstrated that 2–3 mg/kg TFP‐2HCl affects the central nervous system in mice 40–42 . SCH772984 is a selective ERK1/2 inhibitor that binds to unphosphorylated and inactive ERK1/2 and effectively inhibits ERK1/2 phosphorylation 43 .…”

“… 39 Reports have demonstrated that 2–3 mg/kg TFP‐2HCl affects the central nervous system in mice. 40 , 41 , 42 SCH772984 is a selective ERK1/2 inhibitor that binds to unphosphorylated and inactive ERK1/2 and effectively inhibits ERK1/2 phosphorylation. 43 Previous research has reported that the effective dose range of SCH772984 in mouse models is 10–20 mg/kg.…”

Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases

“…Trifluoperazine suppresses the release of cytokines and exerts anticancer effects [38]. Recently, trifluoperazine has been observed to reduce the levels of interleukin-1-beta and TNF-alpha, attenuating the production of proinflammatory mediators [39,40]. Huang et al, (2021) have described that trifluoperazine reduces hypothalamic inflammation in the acute stage by suppressing gliosis induced by saturated fatty acids and inhibiting the protein calmodulin, which binds to Ca+2 in edema brain processes [39,41].…”

“…Recently, trifluoperazine has been observed to reduce the levels of interleukin-1-beta and TNF-alpha, attenuating the production of proinflammatory mediators [39,40]. Huang et al, (2021) have described that trifluoperazine reduces hypothalamic inflammation in the acute stage by suppressing gliosis induced by saturated fatty acids and inhibiting the protein calmodulin, which binds to Ca+2 in edema brain processes [39,41]. Therefore, this drug modulates metabolic dysfunction, where it has been described that its administration has a positive effect on the homeostasis of the glucose pathway [39,42,43].…”

“…Huang et al, (2021) have described that trifluoperazine reduces hypothalamic inflammation in the acute stage by suppressing gliosis induced by saturated fatty acids and inhibiting the protein calmodulin, which binds to Ca+2 in edema brain processes [39,41]. Therefore, this drug modulates metabolic dysfunction, where it has been described that its administration has a positive effect on the homeostasis of the glucose pathway [39,42,43]. Likewise, trifluoperazine has been shown to rescue dopaminergic cells and reduce a particular species of alpha-synuclein, a protein involved in PD [37].…”