Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain

Zhang, Yanbo; Bi, Xiaoying; Adebiyi, Olubunmi A.; Wang, Junhui; Mooshekhian, Ali; Cohen, Jacob; Wei, Zhao; Wang, Fei; Li, Xinmin

doi:10.3389/fphar.2019.00332

Cited by 45 publications

(42 citation statements)

References 53 publications

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“…Therefore, we also demonstrated that anxiety- and depression-like behaviors of CPMS mice were recovered by venlafaxine treatment, which inhibits the 5-HT/noradrenalin synaptosomal uptake [ 40 ]. Venlafaxine also has anti-inflammatory property about abnormal inflammatory responses related to microglia as one of the risk factors causing depressive symptoms [ 41 – 43 ]. So, we confirmed that Velafaxine reduced microglial activation (Additional file 1 : Fig.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-17 induced by cumulative mild stress promoted depression-like behaviors in young adult mice

2021

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The number of young adult patients with major depression, one of the most common mental disorders, is gradually increasing in modern society. Stressful experiences in early life are considered one of the risk factors for chronic depressive symptoms, along with an abnormal inflammatory response in later life. Although increased inflammatory activity has been identified in patients with depression, the cause of long-lasting depressive states is still unclear. To identify the effects of cumulative mild stress in brain development periods, we generated a young adult depression mouse model exposed to cumulative mild stress (CPMS; cumulative mild prenatal stress, mild maternal separation, and mild social defeat) to mimic early life adversities. CPMS mice exhibited more long-lasting anxiety and depression-like behaviors than groups exposed to single or double combinations of mild stress in young adult age. Using the molecular works, we found that inflammatory cytokines, especially interleukin (IL)-17, upregulated microglial activation in the hippocampus, amygdala, and prefrontal cortex of CPMS mice. In the brains of CPMS mice, we also identified changes in the T helper (Th)-17 cell population as well as differentiation. Finally, anti-IL-17 treatment rescued anxiety and depression-like behavior in CPMS mice. In conclusion, we found that cumulative mild stress promoted long-lasting depressive symptoms in CPMS mice through the upregulation of IL-17. We suggest that the CPMS model may be useful to study young adult depression and expect that IL-17 may be an important therapeutic target for depression in young adults.

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Section: Discussionmentioning

confidence: 99%

Interleukin-17 induced by cumulative mild stress promoted depression-like behaviors in young adult mice

2021

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“…FGF22 is expressed mainly in the skin and brain, and the deletion of endogenous FGF22 induced depression-like behavior, as shown by the FST, TST, and SPT (Williams et al, 2016). Recent studies have reported that FGF21 possesses various pharmacological activities including its antioxidant activity, suppression of apoptosis induced by endoplasmic reticulum stress (Liang et al, 2017), and anti-inflammatory activity Zhang et al, 2019). FGF21 weakly binds heparin and can pass through the blood-brain barrier by simple diffusion (Hsuchou et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway

Wang

Zhu

et al. 2020

Front. Pharmacol.

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Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia in vitro. The current study demonstrated that LPS induced depressive-like behaviors, upregulated proinflammatory cytokines, and activated microglia in the mouse hippocampus and activated the inflammatory response in primary microglia, while pretreatment with rhFGF21 markedly improved depression-like behavior deficits, as shown by an increase in the total distance traveled and number of standing numbers in the open field test (OFT) and a decrease in the duration of immobility in the tail suspension test (TST) and forced swimming test (FST). Furthermore, rhFGF21 obviously suppressed expression levels of the proinflammatory cytokines interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6) and inhibited microglial activation and the nuclear factor-kB (NF-kB) signing pathway. Moreover, coadministration of rhFGF21 with the fibroblast growth factor receptor 1 (FGFR1) inhibitor PD173074 significantly reversed these protective effects, indicating that the antidepressant effects of rhFGF21 occur through FGFR1 activation. Taken together, the results of the current study demonstrated for the first time that exogenous rhFGF21 ameliorated LPS-induced depressive-like behavior by inhibiting microglial Frontiers in Pharmacology | www.frontiersin.org February 2020 | Volume 11 | Article 154 1 expression of proinflammatory cytokines through NF-kB suppression. This new discovery suggests rhFGF21 as a new therapeutic candidate for depression treatment.

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“…However, mounting evidence has suggested the existence of various additional targets for these neurotransmitter re-uptake inhibitors, which either support the therapeutic effect, or on the contrary trigger adverse events [24][25][26][27]. Examples include the protection of paroxetine against dyskinesia in Huntingtin mutant mice and nigrostriatal neurodegeneration in Parkinson's disease mouse model [28,29], and the venlafaxine-mediated improvement of cognitive impairment and depressive behavior in multiple sclerosis mouse model [30]. Clinical studies have also found that long-term use of SSRIs may delay conversion from mild cognitive impairment to Alzheimer's dementia in individuals with previous depression [31], and citalopram and sertraline treatment can improve anxiety symptoms of patients with generalized anxiety disorder [32].…”

Section: Discussionmentioning

confidence: 99%

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Liu

Peng

et al. 2020

Preprint

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Background: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. Methods: Primary astrocytes were isolated and cultured using neurobasal-based serum free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses and the underlying mechanisms were analyzed. Results: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. Conclusions: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

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Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain

Cited by 45 publications

References 53 publications

Interleukin-17 induced by cumulative mild stress promoted depression-like behaviors in young adult mice

Interleukin-17 induced by cumulative mild stress promoted depression-like behaviors in young adult mice

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

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