Trazodone treatment protects neuronal-like cells from inflammatory insult by inhibiting NF-κB, p38 and JNK

Abstract

Growing evidence suggests that alterations of the inflammatory/immune system contribute to the pathogenesis of major depression and that inflammatory processes may influence the antidepressant treatment response. Depressed patients exhibit increased levels of inflammatory markers in both the periphery and brain, and high co-morbidity exists between depression and diseases associated with inflammatory alterations. Trazodone (TDZ) is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors. Although the trophic and protective properties of classic antidepressants have extensively been exploited, the effects of TDZ remain to be fully elucidated. In this study, the pharmacological activities of TDZ on human neuronal-like cells were investigated under both physiological and inflammatory conditions. An in vitro inflammatory model was established using lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α), which efficiently mimic the stress-related changes in neurotrophic and pro-inflammatory genes. Our results showed that TDZ significantly increased the mRNA expression of both brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) and decreased the cellular release of the pro-inflammatory cytokine interferon gamma (IFN-γ) in neuronal-like cells. In contrast, neuronal cell treatment with LPS and TNF-α decreased the expression of CREB and BDNF and increased the expression of nuclear factor kappa B (NF-κB), a primary transcription factor that functions in inflammatory response initiation. Moreover, the two agents induced the release of pro-inflammatory cytokines (i.e., interleukin-6 and IFN-γ) and decreased the production of the anti-inflammatory cytokine interleukin-10. TDZ pre-treatment completely reversed the decrease in cell viability and counteracted the decrease in BDNF and CREB expression mediated by LPS-TNF-α. In addition, the production of inflammatory mediators was inhibited, and the release of interleukin-10 was restored to control levels. Furthermore, the intracellular signalling mechanism regulating TDZ-elicited effects was specifically investigated. TDZ induced extracellular signal-regulated kinase (ERK) phosphorylation and inhibited constitutive p38 activation. Moreover, TDZ counteracted the activation of p38 and c-Jun NH2-terminal kinase (JNK) elicited by LPS-TNF-α, suggesting that the neuro-protective role of TDZ could be mediated by p38 and JNK. Overall, our results demonstrated that the protective effects of TDZ under inflammation in neuronal-like cells function by decreasing pro-inflammatory signalling and by enhancing anti-inflammatory signalling.

Inhibition of Acid Sphingomyelinase by Antidepressants Counteracts Stress-Induced Activation of P38-Kinase in Major Depression

“…Further, inhibition of p38K prevented cell death and an inflammatory response of the microglia in these experiments [16]. In accordance with our data preclinical and clinical studies showed an anti-depressive effect of the p38K inhibitors trazodone and iosmapimod and p38K inhibitors are under further investigation and clinical studies for the treatment of major depression [17,18,] https://clinicaltrials.gov/ct2/show/NCT02145468[].…”

PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the prefrontal cortex of mice is involved in the antidepressant‐like effect of pioglitazone

“…32,33 In an in vitro experiment, activated JNK/p38 cascades and apoptosis were observed simultaneously in both neuronal-like cells and PC12 cells exposed to LPS. 34,35 In our study, PIO inhibited the increased phosphorylation of JNK and p38 induced by LPS injection in the mouse PFC. Moreover, in the mouse behavioural analysis, anisomycin (a JNK/p-38 agonist) administration alone had no effect.…”

“…Activation of the JNK/p38 signalling pathway activates Bax to induce apoptosis . In an in vitro experiment, activated JNK/p38 cascades and apoptosis were observed simultaneously in both neuronal‐like cells and PC12 cells exposed to LPS . In our study, PIO inhibited the increased phosphorylation of JNK and p38 induced by LPS injection in the mouse PFC.…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…These conditions include physical and psychological stressful events like exercise, exposure to extreme thermal conditions, different kinds of pain, depression, sleep deprivation, hypoxia, etc. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. In general, an increased IL-10 level during these events is associated with better outcome and adaptation.…”