Retracted: Anti‐inflammatory properties of tianeptine on lipopolysaccharide‐induced changes in microglial cells involve toll‐like receptor‐related pathways

Abstract

Accumulating evidence suggests that activation of microglia plays a key role in the pathogenesis of depression. Activated microglia produce a wide range of factors whose prolonged or excessive release may lead to brain disorders. Thus, the inhibition of microglial cells may be beneficial in the treatment of depressive diseases. Tianeptine is an atypical antidepressant drug with proven clinical efficacy, but its mechanism of action remains still not fully understood. In the present study, using microglial cultures we investigated whether tianeptine modifies microglial activation after lipopolysaccharide (LPS) stimulation and which intracellular pathways are involved in the activity of this antidepressant. Our study shows that tianeptine attenuated the LPS-evoked inflammatory activation of microglia by decreasing the expression of proinflammatory cytokines such as IL-1b, IL-18, IL-6 and tumor necrosis factor a (TNF-a), the release of nitric oxide (NO) and reactive oxygen species (ROS) as well as the expression of inducible nitric oxide synthase. Analyses of signaling pathways demonstrate that tianeptine led to the suppression of LPS-induced TLR4 expression and ERK1/2 phosphorylation. Furthermore, our study reveals the inhibitory impact of tianeptine on caspase-3-induced PKCd degradation and consequently on the activation of NF-jB factor in microglial cells. Taken together, present results show anti-inflammatory properties of tianeptine in microglial cultures stimulated by LPS. This study provides evidence that the inhibition of microglial activation may underlie the therapeutic activity of tianeptine. Keywords: antidepressant drugs, cytokines, inflammation, intracellular pathways, microglia, tianeptine. J. Neurochem. (2016) 136, 958-970. Increasing evidence indicates that microglia, the resident immune cells in the central nervous system (CNS), may be considered the main mediators of inflammation-associated disorders. These cells manage the innate and adaptive immune responses in various pathological processes including brain trauma, ischemia, stroke and infections, as well as during CNS repair (Graeber and Streit 2010;Yang et al. 2011). It has been observed that active microglia can clear Received September 29, 2015; revised manuscript received November 16, 2015; accepted November 17, 2015. Address correspondence and reprint requests to Agnieszka BastaKaim, Department of Experimental Neuroendocrinology, Polish Academy of Sciences, 12 Sme z tna St., 31-343 Krak ow, Poland. E-mail: basta@if-pan.krakow.plAbbreviations used: AP-1, activator protein-1; CD40, cluster of differentiation 40; DCFH, 2 0 ,7 0 -dichlorodihydrofluorescin; DCFH-DA, 2 0 ,7 0 -dichlorofluorescin diacetate; DMEM, Dulbecco's modified Eagle medium; FAM, fluorescein amidite; FBS, fetal bovine serum; HBSS, Hank's Balanced Salt Solution; HPA, hypothalamus-pituitary-adrenal; IL-18, interleukin 18; IL-1b, interleukin 1b; IL-6, interleukin 6; JNK, cJun N-terminal kinase; LDH, lactate dehydrogenase; MCP-1, monocyte chemoattractant protein-1;...

Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation

“…It is well known that LPS is a primary component of endotoxin from Gram-negative bacteria cell walls [43,44], which binds mostly to Toll-like receptor 4 and induces intracellular signaling resulting in the activation of mitogen activated protein kinases (MAPKs) and NF-κB [45]. These proteins have been described as the key regulators of pro-inflammatory factors production such as cytokines and NO, which may have cytotoxic effects and may damage cells [46]. …”

Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain

“…Pathological conditions, such as neuropathic pain states, evoke rapid and profound changes in the morphology, proliferative potential, gene expression and function of the microglial cells. The morphological changes are manifested as an altered cell shape (the microglia revert to an amoeboid appearance) as well as the appearance and rearrangement of surface molecules [16,29,52,75-78]. The microglia respond to various pain-related neuromodulators, but are also capable of directly altering the pain pathways because they express specific receptors that play roles in pain sensitization.…”

“…Another crucial group includes the microglial receptors for hormones and modulators, including the receptors for histamine (H1, H2, H3, H4), opioids (MOP, KOP, NOP), cannabinoids (CB 1 , CB 2 ), substance P (NK-1), neurotrophins (TrkB, TrkC), chemokines (CCR1-7, CXCR1-5, CX 3 CR1), interleukins (IL-1R1/IL-1R2, IL-2R, IL-4R, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, IL-15R, IL-18R), interferons (IFNγR, IFNAR type I), TNFα (TNFR1, TNFR2), and pathogen-associated microbial patterns (Toll-like receptor 1-9 (TLR1-9)) [15, 22, 78, 81, 89-92]. Some of these are mainly ( e.g., TLR2, TLR4, P 2 X 4 ) or exclusively ( e.g., CX 3 CR1) expressed by microglia [93,94].…”

“…In vitro studies have revealed that stimulation with harmful factors ( e.g., lipopolysaccharide (LPS)) moves the cells toward the M1 phenotype and induces the expression of proinflammatory mediators with pro-nociceptive properties. These mediators include IL-1𝛽, IL-6, IL-12, IL-15, IL-18, IFN-γ, TNFα, chemokine (C-C motif) ligands 2, 3, 4, 5, 7 (CCL2, CCL3, CCL4, CCL5, CCL7), cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) [16, 24, 78, 90, 101, 108-112]. However, stimulation with anti-inflam-matory compounds, such as interleukins 4 and 13 (IL-4 and IL-13), promotes the M2 state, deactivates the pro-inflammatory cell phenotype, restores homeostasis and induces the increased expression of mediators with analgesic features (such as IL-1α, IL-1ra, IL-3, IL-10, IL-18BP, tissue inhibitors of metalloproteinases 1 (TIMP1), Arg1, NGF, TGFβ) [16, 24, 90, 109, 111, 113, 114].…”

“…Early studies on the role of MAPK in pain had focused on the neuronal mechanisms of action [116-119]. However, several studies demonstrated profound MAPK activation in microglia [78,120-124] and astrocyte [61,122,123,125]. This process promotes intracellular events that contribute to the peripheral and central sensitization that is manifested at the behavioral and cellular levels [61,120,121,123-127] (Fig.…”