title: 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-1β, IL-18, IL-6 and tumor necrosis factor α (TNF-α), 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 PKCδ degradation and consequently on the activation of NF-κB 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. Our findings show the anti-inflammatory effect of tianeptine (TIA) in lipopolisaccharide (LPS)-stimulated microglial cells. The beneficial tianeptine action is mediated through the inhibition of Toll-like receptor 4 (TLR4) expression as well as the TLR4-related pathways: extracellular signal-regulated kinase 1/2 (ERK1/2), caspase-3-dependent protein kinase δ (PKCδ) cleavage and the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings may provide a new therapeutic strategy for treatment of disorders based on neuroinflammation, including depression.
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Slusarczyk
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Trojan
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Glombik
authors.affiliation: Department of Pharmacology of Pain, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Piotrowska
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Boguslawa
authors.initials: B
authors.lastname: Budziszewska
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Kubera
authors.affiliation: Department of Pharmacology of Pain, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Popiolek-Barczyk
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Wladyslaw
authors.initials: W
authors.lastname: Lason
authors.affiliation: Department of Pharmacology of Pain, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.affiliation: Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Basta-Kaim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013841:Thiazepines / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013841:Thiazepines; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C050504:tianeptine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: antidepressant drugs; cytokines; inflammation; intracellular pathways; microglia; tianeptine