The anti-inflammatory activity of duloxetine, a serotonin/norepinephrine reuptake inhibitor, prevents kainic acid-induced hippocampal neuronal death in mice

Choi, Hee‐Soo; Park, Joon Ha; Ahn, Ji Hyeon; Hong, Seongkweon; Cho, Jun Hwi; Won, Moo‐Ho; Lee, Choong‐Hyun

doi:10.1016/j.jns.2015.10.001

Cited by 27 publications

(19 citation statements)

References 55 publications

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“…Duloxetine (DXT), a potent and balanced serotonin/norepinephrine reuptake inhibitor (SNRI), has been used in the treatment of major depressive disorders, painful diabetic neuropathy and urinary incontinence ( Nemeroff et al ., 2002 ; Goldstein et al ., 2005 ; Guay, 2005 ). Recently, we showed that DXT had a neuroprotective effect against kainic acid-induced excitotoxic neuronal death in the mouse hippocampus, and that the neuroprotective effect of DXT was related with its anti-inflammatory action ( Choi et al ., 2015 ). In addition, we also reported that a neuroprotective effect of DXT was closely related with decreases of glial activation and oxidative stress in the hippocampal CA1 region following transient global cerebral ischemia ( Lee et al ., 2016b ).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Duloxetine on Chronic Cerebral Hypoperfusion-Induced Hippocampal Neuronal Damage

Park

Lee

2018

Biomolecules & Therapeutics

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Chronic cerebral hypoperfusion (CCH), which is associated with onset of vascular dementia, causes cognitive impairment and neuropathological alterations in the brain. In the present study, we examined the neuroprotective effect of duloxetine (DXT), a potent and balanced serotonin/norepinephrine reuptake inhibitor, on CCH-induced neuronal damage in the hippocampal CA1 region using a rat model of permanent bilateral common carotid arteries occlusion. We found that treatment with 20 mg/kg DXT could attenuate the neuronal damage, the reduction of phosphorylations of mTOR and p70S6K as well as the elevations of TNF-α and IL-1β levels in the hippocampal CA1 region at 28 days following CCH. These results indicate that DXT displays the neuroprotective effect against CCH-induced hippocampal neuronal death, and that neuroprotective effect of DXT may be closely related with the attenuations of CCH-induced decrease of mTOR/p70S6K signaling pathway as well as CCH-induced neuroinflammatory process.

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Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Duloxetine on Chronic Cerebral Hypoperfusion-Induced Hippocampal Neuronal Damage

Park

Lee

2018

Biomolecules & Therapeutics

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“…Previous studies suggested that PNS predisposes for increased hippocampal immune response and enhances microglial and astroglial activation when the organism is exposed to a pro‐inflammatory challenge in adult life (Diz‐Chaves et al, 2013). Moreover, duloxetine treatment may suppress the kainic acid‐induced activations of microglia and astrocytes as well as kainic acid‐induced increases of TNF‐α and IL‐1β levels (Choi et al, 2015). Coupled with the interaction of the HPA axis and pro‐inflammatory cytokines, PNS may exert a long‐term impact on the offspring while duloxetine treatment may prevent the harmful consequences in the offspring induced by PNS.…”

Section: Discussionmentioning

confidence: 99%

“…Antidepressants modulate cytokine production, especially tricyclics and selective serotonin reuptake inhibitors (SSRIs), but the influence of serotonin and norepinephrine inhibitors (SNRIs) on cytokine levels has not been extensively studied. The versatile SNRI duloxetine can effectively treat diabetic neuropathic pain, stress urinary incontinence and depression (Choi et al, 2015). In past studies, it has been reported that some SNRIs have anti‐inflammatory effects, asmirtazapine decreased IL‐6 levels (Kubera et al, 2006), venlafaxine inhibited TNF‐α production (Tynan et al, 2012), and duloxetine increased IL‐10 levels (Ohgi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Duloxetine prevents the effects of prenatal stress on depressive‐like and anxiety‐like behavior and hippocampal expression of pro‐inflammatory cytokines in adult male offspring rats

Zhang

Wang

et al. 2016

Intl J of Devlp Neuroscience

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Stress during pregnancy may cause neurodevelopmental and psychiatric disorders. However, the mechanisms are largely unknown. Currently, pro-inflammatory cytokines have been identified as a risk factor for depression and anxiety disorder. Unfortunately, there is very little research on the long-term effects of prenatal stress on the neuroinflammatory system of offspring. Moreover, the relationship between antidepressant treatment and cytokines in the central nervous system, especially in the hippocampus, an important emotion modulation center, is unclear. Therefore, the aim of this study was to determine the effects of prenatal chronic mild stress during development on affective-like behaviors and hippocampal cytokines in adult offspring, and to verify whether antidepressant (duloxetine) administration from early adulthood could prevent the harmful consequences. To do so, prenatally stressed and non-stressed Sprague-Dawley rats were treated with either duloxetine (10mg/kg/day) or vehicle from postnatal day 60 for 21days. Adult offspring were divided into four groups: 1) prenatal stress+duloxetine treatment, 2) prenatal stress+vehicle, 3) duloxetine treatment alone, and 4) vehicle alone. Adult offspring were assessed for anxiety-like behavior using the open field test and depression-like behavior using the forced swim test. Brains were analyzed for pro-inflammatory cytokine markers in the hippocampus via real-time PCR. Results demonstrate that prenatal stress-induced anxiety- and depression-like behaviors are associated with an increase in hippocampal inflammatory mediators, and duloxetine administration prevents the increased hippocampal pro-inflammatory cytokine interleukin-6 and anxiety- and depression-like behavior in prenatally stressed adult offspring. This research provides important evidence on the long-term effect of PNS exposure during development in a model of maternal adversity to study the pathogenesis of depression and its therapeutic interventions.

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“…In vivo, most of the literature has indicated that duloxetine had a neuro-protective effect in animal models. The mechanisms involved included upregulation of brain-derived neurotrophic factor (BDNF) (Mannari et al 2008 ), an anti-inflammatory effect (Choi et al 2015 ) and suppression of the glial functions (Tawfik et al 2018 ), but it was stated that duloxetine did not result in any physiological effect on neurogenesis (Marlatt et al 2010 ). In vitro, duloxetine protected cultured neurons (Demirdas et al 2017 ) and neural cells (Akpinar et al 2014 ) against stress induced by oxidative stress, apoptosis, and Ca 2+ entry.…”

Section: Introductionmentioning

confidence: 99%

Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells

et al. 2020

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Duloxetine is a clinical drug that is primarily used for treatment of depression and pain, but it has side effects of addiction and tolerance. Cytochrome P450 (CYP) is its metabolic enzyme, and the drug’s biofunction results from its neuro-protective effect in animal and cell models. We aimed to investigate the duloxetine-induced neural cytotoxicity effect and its performance in an N2a cell neurite outgrowth model. Cell death was assessed as cell viability using a Cell Count Kit-8 and further evaluated using bright-field images, propidium iodide (PI) and annexin V staining, colony-formation analysis, TUNEL staining of the cells, and biochemical testing. N2a cells were committed to differentiation by serum withdrawal and RA induction, and the neurite outgrowth was evaluated as the number of differentiated cells, longest neurite length, and average neurite length. Cell cycle analysis, PI and annexin V staining, mRNA expression, and biochemical testing were used to evaluate the drug effects on differentiation. The induction of neural cell death by duloxetine was not affected by classic cell death inhibitors but was promoted by the CYP inducer rifampicin. N2a cell neurite outgrowth was promoted by duloxetine via reduction of the CYP2D6 and MDA levels and induction of Bdnf protein levels. Duloxetine induces neural cell death through effects on CYP and promotes N2a cell neurite outgrowth by regulating CYP, Bdnf protein, and the intracellular lipid peroxidation level.

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The anti-inflammatory activity of duloxetine, a serotonin/norepinephrine reuptake inhibitor, prevents kainic acid-induced hippocampal neuronal death in mice

Cited by 27 publications

References 55 publications

Neuroprotective Effect of Duloxetine on Chronic Cerebral Hypoperfusion-Induced Hippocampal Neuronal Damage

Neuroprotective Effect of Duloxetine on Chronic Cerebral Hypoperfusion-Induced Hippocampal Neuronal Damage

Duloxetine prevents the effects of prenatal stress on depressive‐like and anxiety‐like behavior and hippocampal expression of pro‐inflammatory cytokines in adult male offspring rats

Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells

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