Abstract
BackgroundIn the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up-regulating inflammatory processes. Reactive astrocytes and microglia are associated with the pathophysiology of neuronal injury, neurodegenerative diseases and major depression, in both animal models and human brains. Several studies have reported clear anti-inflammatory effects of anti-depressant treatment on astrocytes, especially in models of neurological disorders. Trazodone (TDZ) is a triazolopyridine derivative that is structurally unrelated to other major classes of antidepressants. Although the molecular mechanisms of TDZ in neurons have been investigated, it is unclear whether astrocytes are also a TDZ target.MethodsThe effects of TDZ on human astrocytes were investigated in physiological conditions and following inflammatory insult with lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α). Astrocytes were assessed for their responses to pro-inflammatory mediators and cytokines, and the receptors and signalling pathways involved in TDZ-mediated effects were evaluated.ResultsTDZ had no effect on cell proliferation, but it decreased pro-inflammatory mediator release and modulated trophic and transcription factor mRNA expression. Following TDZ treatment, the AKT pathway was activated, whereas extracellular signal-regulated kinase and c-Jun NH2-terminal kinase were inhibited. Most importantly, a 72-h TDZ pre-treatment before inflammatory insult completely reversed the anti-proliferative effects induced by LPS-TNF-α. The expression or the activity of inflammatory mediators, including interleukin-6, c-Jun NH2-terminal kinase and nuclear factor κB, were also reduced. Furthermore, TDZ affected astrocyte metabolic support to neurons by counteracting the inflammation-mediated lactate decrease. Finally, TDZ protected neuronal-like cells against neurotoxicity mediated by activated astrocytes. These effects mainly involved an activation of 5-HT1A and an antagonism at 5-HT2A/C serotonin receptors. Fluoxetine, used in parallel, showed similar final effects nevertheless it activates different receptors/intracellular pathways.ConclusionsAltogether, our results demonstrated that TDZ directly acts on astrocytes by regulating intracellular signalling pathways and increasing specific astrocyte-derived neurotrophic factor expression and lactate release. TDZ may contribute to neuronal support by normalizing trophic and metabolic support during neuroinflammation, which is associated with neurological diseases, including major depression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0446-x) contains supplementary material, which is available to authorized users.
Highlights
In the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up-regulating inflammatory processes
Effect of TDZ treatment on astrocyte proliferation To verify whether TDZ treatment affected astrocyte proliferation, human cells were treated with different concentrations of the drug (1 nM-10 μM) for 24 or 72 h
Under physiological conditions TDZ significantly upregulated brain-derived nerve factor (BDNF) and cAMP response element-binding protein (CREB) after 24 h, consistent with data obtained with FLUOX or those previously reported for selective serotonin reuptake inhibitor (SSRI) in primary cortical astrocyte cultures [25], confirming that these factors may contribute to the therapeutic action of anti-depressant drugs in a b astrocytes
Summary
In the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up-regulating inflammatory processes. Reactive astrocytes and microglia are associated with the pathophysiology of neuronal injury, neurodegenerative diseases and major depression, in both animal models and human brains. Astrocytes are the primary glial cell type in the brain and maintain CNS homeostasis; they promptly respond to injury and regulate neuroinflammatory events [2,3,4] and are promising targets for modulating neuroinflammation. Both in vitro and in vivo studies have shown that astrocytes produce various cytokines, neurotrophic and growth factors [5,6,7,8]. Preclinical studies have shown that glial cell loss in the rat prefrontal cortex is sufficient to induce depressive-like behaviours [20]
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