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Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes.

Daniele S, Zappelli E, Martini C - J Neuroinflammation (2015)

Bottom Line: TDZ had no effect on cell proliferation, but it decreased pro-inflammatory mediator release and modulated trophic and transcription factor mRNA expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano, 6, Pisa, 56126, PI, Italy. simona.daniele@for.unipi.it.

ABSTRACT

Background: 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. 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.

Methods: The 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.

Results: TDZ 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.

Conclusions: Altogether, 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.

No MeSH data available.


Related in: MedlinePlus

The possible intracellular route of TDZ in human astrocytes. Schematic overview of the possible TDZ/ERK/AKT/JNK signalling pathways in our experimental model is depicted. In astrocytes, the 5-HT1AR is coupled to Gαi/o proteins [83]; its activation by TDZ decreases ERK phosphorylation via Gαi/o protein ([a]) [84, 85], and increases AKT phosphorylation ([b]) [92, 93]. The PI3K/AKT pathway may contribute to deregulate JNK. Moreover, AKT phosphorylates GSK3, blocking in turn its activity, leading to alteration of astrocyte metabolism ([c]) [92, 93]. TDZ enhances CREB and BDNF transcription via a PI3K/AKT pathway ([d]). 5-HT2A/CRs may couple to Gαq proteins [40]; TDZ, showing an antagonistic activity on 5HT2A/CRs, may reduce ERK activation ([e]). TDZ antagonizes α-ARs ([f]), contributing to reduce JNK phosphorylation. Abbreviations: AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; PKC: protein kinase C; CREB: cAMP response element-binding protein; BDNF: brain-derived nerve factor; ERK: extracellular signal-regulated kinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; GSK3: glycogen synthase kinase 3; PDK1: 3-phosphoinositide dependent protein kinase-1; JNKs: c-Jun N-terminal kinases; PLC: Phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol trisphosphate; DAG: diacyl-glycerol
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Fig14: The possible intracellular route of TDZ in human astrocytes. Schematic overview of the possible TDZ/ERK/AKT/JNK signalling pathways in our experimental model is depicted. In astrocytes, the 5-HT1AR is coupled to Gαi/o proteins [83]; its activation by TDZ decreases ERK phosphorylation via Gαi/o protein ([a]) [84, 85], and increases AKT phosphorylation ([b]) [92, 93]. The PI3K/AKT pathway may contribute to deregulate JNK. Moreover, AKT phosphorylates GSK3, blocking in turn its activity, leading to alteration of astrocyte metabolism ([c]) [92, 93]. TDZ enhances CREB and BDNF transcription via a PI3K/AKT pathway ([d]). 5-HT2A/CRs may couple to Gαq proteins [40]; TDZ, showing an antagonistic activity on 5HT2A/CRs, may reduce ERK activation ([e]). TDZ antagonizes α-ARs ([f]), contributing to reduce JNK phosphorylation. Abbreviations: AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; PKC: protein kinase C; CREB: cAMP response element-binding protein; BDNF: brain-derived nerve factor; ERK: extracellular signal-regulated kinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; GSK3: glycogen synthase kinase 3; PDK1: 3-phosphoinositide dependent protein kinase-1; JNKs: c-Jun N-terminal kinases; PLC: Phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol trisphosphate; DAG: diacyl-glycerol

Mentions: Consistent with literature data [64, 78], FLUOX significantly activated ERK1/2 by a 5-HT2BR-mediated mechanism. Surprisingly, TDZ inhibited basal ERK activity, via activation of 5-HT1ARs and blockage of 5-HT2A/CRs (Fig. 14). 5-HT1ARs couple to inhibitory G-proteins, resulting in decreased cAMP production and PKA activity [79], but the regulation of ERK activity by these receptors in brain is divergent and complicated [80]. Consistent with our finding, some papers have reported 5-HT1AR activation decreases ERK phosphorylation in the hippocampus [81–83]. The TDZ-mediated decrease of ERK suggests that this anti-depressant modulates CREB and BDNF transcription via a different, ERK-independent, mechanism. Consistent with this hypothesis, TDZ enhancement of CREB and BDNF mRNA levels was counteracted by a PI3K inhibitor. Similarly, an involvement of PI3K in BDNF promoter activation and in the related CREB transcription has been reported also for other mood stabilizers, such as lithium or valproate [84–86]. Moreover, melatonin has been demonstrated to modulate CREB and GDNF expression in primary astrocytes by a PI3K/AKT mechanism [87].Fig. 14


Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes.

Daniele S, Zappelli E, Martini C - J Neuroinflammation (2015)

The possible intracellular route of TDZ in human astrocytes. Schematic overview of the possible TDZ/ERK/AKT/JNK signalling pathways in our experimental model is depicted. In astrocytes, the 5-HT1AR is coupled to Gαi/o proteins [83]; its activation by TDZ decreases ERK phosphorylation via Gαi/o protein ([a]) [84, 85], and increases AKT phosphorylation ([b]) [92, 93]. The PI3K/AKT pathway may contribute to deregulate JNK. Moreover, AKT phosphorylates GSK3, blocking in turn its activity, leading to alteration of astrocyte metabolism ([c]) [92, 93]. TDZ enhances CREB and BDNF transcription via a PI3K/AKT pathway ([d]). 5-HT2A/CRs may couple to Gαq proteins [40]; TDZ, showing an antagonistic activity on 5HT2A/CRs, may reduce ERK activation ([e]). TDZ antagonizes α-ARs ([f]), contributing to reduce JNK phosphorylation. Abbreviations: AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; PKC: protein kinase C; CREB: cAMP response element-binding protein; BDNF: brain-derived nerve factor; ERK: extracellular signal-regulated kinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; GSK3: glycogen synthase kinase 3; PDK1: 3-phosphoinositide dependent protein kinase-1; JNKs: c-Jun N-terminal kinases; PLC: Phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol trisphosphate; DAG: diacyl-glycerol
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4666178&req=5

Fig14: The possible intracellular route of TDZ in human astrocytes. Schematic overview of the possible TDZ/ERK/AKT/JNK signalling pathways in our experimental model is depicted. In astrocytes, the 5-HT1AR is coupled to Gαi/o proteins [83]; its activation by TDZ decreases ERK phosphorylation via Gαi/o protein ([a]) [84, 85], and increases AKT phosphorylation ([b]) [92, 93]. The PI3K/AKT pathway may contribute to deregulate JNK. Moreover, AKT phosphorylates GSK3, blocking in turn its activity, leading to alteration of astrocyte metabolism ([c]) [92, 93]. TDZ enhances CREB and BDNF transcription via a PI3K/AKT pathway ([d]). 5-HT2A/CRs may couple to Gαq proteins [40]; TDZ, showing an antagonistic activity on 5HT2A/CRs, may reduce ERK activation ([e]). TDZ antagonizes α-ARs ([f]), contributing to reduce JNK phosphorylation. Abbreviations: AC: adenylyl cyclase; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A; PKC: protein kinase C; CREB: cAMP response element-binding protein; BDNF: brain-derived nerve factor; ERK: extracellular signal-regulated kinase; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; GSK3: glycogen synthase kinase 3; PDK1: 3-phosphoinositide dependent protein kinase-1; JNKs: c-Jun N-terminal kinases; PLC: Phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol trisphosphate; DAG: diacyl-glycerol
Mentions: Consistent with literature data [64, 78], FLUOX significantly activated ERK1/2 by a 5-HT2BR-mediated mechanism. Surprisingly, TDZ inhibited basal ERK activity, via activation of 5-HT1ARs and blockage of 5-HT2A/CRs (Fig. 14). 5-HT1ARs couple to inhibitory G-proteins, resulting in decreased cAMP production and PKA activity [79], but the regulation of ERK activity by these receptors in brain is divergent and complicated [80]. Consistent with our finding, some papers have reported 5-HT1AR activation decreases ERK phosphorylation in the hippocampus [81–83]. The TDZ-mediated decrease of ERK suggests that this anti-depressant modulates CREB and BDNF transcription via a different, ERK-independent, mechanism. Consistent with this hypothesis, TDZ enhancement of CREB and BDNF mRNA levels was counteracted by a PI3K inhibitor. Similarly, an involvement of PI3K in BDNF promoter activation and in the related CREB transcription has been reported also for other mood stabilizers, such as lithium or valproate [84–86]. Moreover, melatonin has been demonstrated to modulate CREB and GDNF expression in primary astrocytes by a PI3K/AKT mechanism [87].Fig. 14

Bottom Line: TDZ had no effect on cell proliferation, but it decreased pro-inflammatory mediator release and modulated trophic and transcription factor mRNA expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Pisa, Via Bonanno Pisano, 6, Pisa, 56126, PI, Italy. simona.daniele@for.unipi.it.

ABSTRACT

Background: 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. 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.

Methods: The 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.

Results: TDZ 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.

Conclusions: Altogether, 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.

No MeSH data available.


Related in: MedlinePlus