Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways

Yang, Mengqi; Dang, Ruili; Xu, Pengfei; Guo, Yujin; Han, Wenxiu; Liao, Dehua; Jiang, Pei

doi:10.1007/s00213-018-4949-x

Cited by 42 publications

(44 citation statements)

References 52 publications

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“…An increasing number of studies have suggested that inflammation plays a crucial role in the process of MDD (Rush et al, 2016;Yang M. et al, 2018). The activation of microglia, a kind of macrophage in the brain, can trigger the expression of proinflammatory cytokines involved in the pathological development of neuroinflammation-and degeneration-related diseases.…”

Section: Discussionmentioning

confidence: 99%

“…LPS administration induced depression-like behaviors, triggered microglial activation in the hippocampus, and upregulated proinflammatory cytokine expression (Brites and Fernandes, 2015). Activated microglia are the major source of proinflammatory cytokines, such as TNF-a, IL-1b, and IL-6, in the CNS (Yang M. et al, 2018). Preclinical and clinical studies have proposed that proinflammatory cytokines are associated with the pathogenesis of depression (Karson et al, 2013) and that an increase in pro-inflammatory cytokines contributes to depressive-like behaviors (Raison et al, 2006;Guo et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Under normal conditions, NF-kB is bound to the inhibitor IkB, and exists in an inactive state in the cellular cytoplasm. However, once activated by an activator, such as LPS, NF-kB is phosphorylated to p-NF-kB, which is then released and translocated into the nucleus, where it promotes the expression of inflammatory cytokines (Luo et al, 2014;Yang M. et al, 2018). In the current study, we examined nuclear and cytoplasmic levels of NF-kB in the hippocampus of an LPSinduced depression mouse model and determined the expression levels of NF-kB and p-NF-kB in LPS-induced primary microglia to assess the effects of rhFGF21 on the NF-kB signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The NF-kB signaling pathway is involved in inflammatory events. Once stimulated by LPS, NF-kB is phosphorylated and activated, and phosphorylated NF-kB translocates into the nucleus and binds a consensus sequence in targeted genes to regulate the expression of inflammatory cytokines such as TNF-a, IL-6, and IL-1b (Yang M. et al, 2018). Therefore, we speculated that the anti-depressive effect of rhFGF21 is mediated by NF-kB signaling pathway regulation.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wang

Zhu

et al. 2020

Front. Pharmacol.

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“…The paradigm of forced swim test (FST) is based upon the evaluation of immobility, as a measure of behavioral despair in stressful and inescapable situations [13]. In brief, each rat was placed in a glass cylinder (45 cm height, 25 cm diameter) which contained approximately 35 cm of water (24 ± 1°C) for 15 min.…”

Section: Behavioral Testsmentioning

confidence: 99%

Antidepressant activity of ω-3 polyunsaturated fatty acids in ovariectomized rats: role of neuroinflammation and microglial polarization

Song

Zhang

et al. 2020

Lipids Health Dis

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Background: Menopause predisposes individuals to affective disorders, such as depression, which is tightly related to neuroinflammation. While the neuroinflammatory condition has been demonstrated in ovariectomized (OVX) rodents, there is limited evidence concerning microglial polarization, a key process in brain immune activation, in menopause-related brain. Methods: Therefore, the present study aims to evaluate the polarized microglia in long-term OVX rats and we further explored whether supplementation of ω-3 polyunsaturated fatty acids (PUFA), the pleiotropic bioactive nutrient, is effective in the neurobehavioral changes caused by OVX. Results: Our data showed that OVX-induced anxiety and depression-like behaviors in rats, accompanied with increased neural apoptosis and microglial activation in the hippocampus. Additionally, OVX enhanced proinflammatory cytokines expression and suppressed the expression of anti-inflammatory cytokine, IL-10. Correspondingly, OVX reinforced NFκB signaling and shifted the microglia from immunoregulatory M2 phenotype to proinflammatory M1 phenotype. Meanwhile, daily supplementation with PUFA suppressed microglial M1 polarization and potentiated M2 polarization in OVX rats. In parallel, PUFA also exerted antidepressant and neuroprotective activities, accompanied with neuroimmune-modulating actions. Conclusion: Collectively, the present study firstly demonstrated the disturbed microglial polarization in the OVX brain and provide novel evidence showing the association between the antidepressant actions of PUFA and the restraint neuroinflammatory progression.

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Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke

et al. 2023

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ImportanceDL-3-n-butylphthalide (NBP) is a drug for treating acute ischemic stroke and may play a neuroprotective role by acting on multiple active targets. The efficacy of NBP in patients with acute ischemic stroke receiving reperfusion therapy remains unknown.ObjectiveTo assess the efficacy and safety of NBP in patients with acute ischemic stroke receiving reperfusion therapy of intravenous thrombolysis and/or endovascular treatment.Design, Setting, and ParticipantsThis multicenter, double-blind, placebo-controlled, parallel randomized clinical trial was conducted in 59 centers in China with 90-day follow-up. Of 1236 patients with acute ischemic stroke, 1216 patients 18 years and older diagnosed with acute ischemic stroke with a National Institutes of Health Stroke Scale score ranging from 4 to 25 who could start the trial drug within 6 hours from symptom onset and received either intravenous recombinant tissue plasminogen activator (rt-PA) or endovascular treatment or intravenous rt-PA bridging to endovascular treatment were enrolled, after excluding 20 patients who declined to participate or did not meet eligibility criteria. Data were collected from July 1, 2018, to May 22, 2022.InterventionsWithin 6 hours after symptom onset, patients were randomized to receive NBP or placebo in a 1:1 ratio.Main Outcomes and MeasuresThe primary efficacy outcome was the proportion of patients with a favorable outcome based on 90-day modified Rankin Scale score (a global stroke disability scale ranging from 0 [no symptoms or completely recovered] to 6 [death]) thresholds of 0 to 2 points, depending on baseline stroke severity.ResultsOf 1216 enrolled patients, 827 (68.0%) were men, and the median (IQR) age was 66 (56-72) years. A total of 607 were randomly assigned to the butylphthalide group and 609 to the placebo group. A favorable functional outcome at 90 days occurred in 344 patients (56.7%) in the butylphthalide group and 268 patients (44.0%) in the placebo group (odds ratio, 1.70; 95% CI, 1.35-2.14; P &lt; .001). Serious adverse events within 90 days occurred in 61 patients (10.1%) in the butylphthalide group and 73 patients (12.0%) in the placebo group.Conclusions and RelevanceAmong patients with acute ischemic stroke receiving intravenous thrombolysis and/or endovascular treatment, NBP was associated with a higher proportion of patients achieving a favorable functional outcome at 90 days compared with placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT03539445

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Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways

Abstract: These results provide more insight into pathogenesis of MDD and firstly demonstrated the potential antidepressant actions of NBP.

Cited by 42 publications

References 52 publications

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

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

Antidepressant activity of ω-3 polyunsaturated fatty acids in ovariectomized rats: role of neuroinflammation and microglial polarization

Efficacy and Safety of Butylphthalide in Patients With Acute Ischemic Stroke

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