Inhibition of IL-6 methylation by Saikosaponin C regulates neuroinflammation to alleviate depression

Bai, Zijun; Gao, Tiantian; Zhang, Rui; Lu, You-Yuan; Tian, Jinlong; Wang, Tao; Zhao, Keke; Wang, Hanqing

doi:10.1016/j.intimp.2023.110043

Cited by 12 publications

(6 citation statements)

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“…Progressive neuroinflammation plays a primary role in the cognitive impairment related with neurodegenerative diseases such as Alzheimer's disease and Huntington's disease (Bains et al., 2022 ; Decandia et al., 2023 ). Neuroinflammation influences cell proliferation and differentiation, synaptic plasticity, and cognitive function (Bai et al., 2023 ; Cangalaya et al., 2023 ). The levels of pro‐inflammatory cytokines were found to be increased in the peripheral blood of patients with sleep disorders (Irwin et al., 2016 ; Xia et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice

Zhang,

Wang,

Wei

et al. 2024

Brain and Behavior

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BackgroundThe inflammation and synaptic dysfunction induced by mitochondrial dysfunction play essential roles in the learning and memory impairment associated with sleep dysfunction. Elamipretide (SS‐31), a novel mitochondrion‐targeted antioxidant, was proven to improve mitochondrial dysfunction, the inflammatory response, synaptic dysfunction, and cognitive impairment in models of cerebral ischemia, sepsis, and type 2 diabetes. However, the potential for SS‐31 to improve the cognitive impairment induced by chronic sleep deprivation (CSD) and its underlying mechanisms is unknown.MethodsAdult c57BL/6J mice were subjected to CSD for 21 days using an activity wheel accompanied by daily intraperitoneal injection of SS‐31 (5 mg/kg). The novel object recognition and Morris water maze test were used to evaluate hippocampus‐dependent cognitive function. Western blotting and reverse transcription‐quantitative polymerase chain reaction assays were used to determine the effects of CSD and SS‐31 on markers of mitochondria, inflammation response, and synaptic function. Enzyme‐linked immunosorbent assays were used to examine the levels of proinflammatory cytokines.ResultsSS‐31 could improve the cognitive impairment induced by CSD. In particular, SS‐31 treatment restored the CSD‐induced decrease in sirtuin 1 (SIRT1) and peroxisome proliferator‐activated receptor γ coactivator alpha levels and the increase in levels nuclear factor kappa‐B and inflammatory cytokines, including interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐alpha. Furthermore, SS‐31 significantly increased the levels of brain‐derived neurotrophic factor, postsynaptic density protein‐95, and synaptophysin in CSD mice.ConclusionTaken together, these results suggest that SS‐31 could improve CSD‐induced mitochondrial biogenesis dysfunction, inflammatory response, synaptic dysfunction, and cognitive impairment by increasing SIRT1 expression levels.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice

Zhang,

Wang,

Wei

et al. 2024

Brain and Behavior

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“…IL-6, a common inflammatory factor, is involved in the pathogenesis of MDD through various mechanisms. IL-6 can cross the blood–brain barrier (BBB)and increase synaptic contractility by directly affecting neurons or regulating microglia and other immune cells, thereby aggravating depression [ 23 , 24 ]. Secondly, IL-6 can directly affect brain function and neurotransmitter production, leading to the progression and poor prognosis of MDD [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Associations between serum estradiol and IL-6/sIL-6R/sgp130 complex in female patients with major depressive disorder

Sun,

Chen,

Mei

et al. 2023

BMC Psychiatry

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Background It has been hypothesized that the IL-6/sIL-6R/sgp130 complex, an inflammatory complex, plays a critical role in the pathogenesis of major depressive disorder (MDD). Estradiol (E2) is a sex steroid hormone involved in emotional regulation and MDD. This study aimed to investigate the relationship between E2 and IL-6/sIL-6R/sgp130 complex in patients with MDD. Methods Using enzyme-linked immunosorbent assay, the levels of IL-6, sIL-6Rα, and sgp130 were compared between 117 female patients with MDD and 122 healthy controls.The serum concentrations of E2 and other biomarkers were also measured. Results (1) The serum levels of IL-6 and sIL-6Rα in patients with MDD were significantly higher than those in the control group, while the serum levels of sgp130 and E2 were significantly lower (all P < 0.05). (2) Low levels of E2 were associated with high levels of IL-6 and low levels of sgp130 (all P < 0.01). (3) HAMD-24 score was positively correlated with the serum level of IL-6, but negatively correlated with the serum levels of sgp130 and E2(all P < 0.05). (4) IL-6 and sgp130 had certain prognostic values in MDD, and the combination of various indicators showed a significantly superior prognostic value. Conclusions The IL6/sIL-6R/sgp130 complex in female patients with MDD was closely related to E2 level. In addition, IL-6 and sgp130 may be valuable serum biomarkers for the diagnosis and prognosis of MDD in women.

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“…Similarly, rodent studies found fluoxetine reduced the CUMS elevated IL-1β in rat PFC ( Pan et al, 2014 ), and the LPS elevated IL-1β, IL-6 and TNF-α in mouse hippocampus ( Duda et al, 2017 ). On the other hand, drugs with anti-inflammatory properties, such as the Geraniol, Sinomenine, Patchouli alcohol, Baicalin and Berberine, alleviated the the CUMS and corticosterone-induced depressive-like behaviors in mice, respectively ( Bai et al, 2023 ; Deng et al, 2015 ; He et al, 2023 ; L. T. Guo et al, 2019 ; Liu et al, 2018 ; Qin et al, 2023 ). Patchouli alcohol and Berberine take effect through inhibiting the NLRP3-mediated neuroinflammation ( He et al, 2023 ; Qin et al, 2023 ), while Baicalin takes effect through inhibiting the toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway ( L. T. Guo et al, 2019 ).…”

Section: The Underlying Mechanisms Of Os-induced Depressionmentioning

confidence: 99%

“…Patchouli alcohol and Berberine take effect through inhibiting the NLRP3-mediated neuroinflammation ( He et al, 2023 ; Qin et al, 2023 ), while Baicalin takes effect through inhibiting the toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway ( L. T. Guo et al, 2019 ). A recent study further showed Saikosaponin C alleviated the chronic social defeated stress (CSDS)-induced depressive-like behaviors in mice, through inhibiting the IL-6 methylation, which indicates the prominent role of epigenetic modulation of pro-inflammatory cytokines in depression ( Bai et al, 2023 ). The above evidence indicates neuroinflammation as an important pathogenesis of depression, and suggests anti-inflammation as a potentially effective remedy avenue.…”

Section: The Underlying Mechanisms Of Os-induced Depressionmentioning

confidence: 99%

“…Furthermore, antidepressants fluoxetine and Chinese herbal formula Xiao-Yao-San reversed depressive-like behaviors, through upregulating the CUMS inhibited GLT-1 expression in mice ( Ding et al, 2017 ; Liu et al, 2019 ). In addition, the glutamatergic signal inhibitory drugs alleviated depressive-like behaviors, such as the GLT-1 promoting drug Riluzole ( Banasr et al, 2010 ), and a variety of NMDA receptor antagonists ( Autry et al, 2011 ). However, NMDA receptor antagonists, such as phencyclidine and dizocilpine, could impair cognitive function, which precludes its utilization as antidepressants ( B. Zhang et al, 2019 ; Zhang et al, 2017 ).…”

Section: The Underlying Mechanisms Of Os-induced Depressionmentioning

confidence: 99%

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How Oxidative Stress Induces Depression?

Lei

Chen

et al. 2023

ASN Neuro

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Depression increasingly affects a wide range and a large number of people worldwide, both physically and psychologically, which makes it a social problem requiring prompt attention and management. Accumulating clinical and animal studies have provided us with substantial insights of disease pathogenesis, especially central monoamine deficiency, which considerably promotes antidepressant research and clinical treatment. The first-line antidepressants mainly target the monoamine system, whose drawbacks mainly include slow action and treatment resistant. The novel antidepressant esketamine, targeting on central glutamatergic system, rapidly and robustly alleviates depression (including treatment-resistant depression), whose efficiency is shadowed by potential addictive and psychotomimetic side effects. Thus, exploring novel depression pathogenesis is necessary, for seeking more safe and effective therapeutic methods. Emerging evidence has revealed vital involvement of oxidative stress (OS) in depression, which inspires us to pursue antioxidant pathway for depression prevention and treatment. Fully uncovering the underlying mechanisms of OS-induced depression is the first step towards the avenue, thus we summarize and expound possible downstream pathways of OS, including mitochondrial impairment and related ATP deficiency, neuroinflammation, central glutamate excitotoxicity, brain-derived neurotrophic factor/tyrosine receptor kinase B dysfunction and serotonin deficiency, the microbiota-gut-brain axis disturbance and hypothalamic-pituitary-adrenocortical axis dysregulation. We also elaborate on the intricate interactions between the multiple aspects, and molecular mechanisms mediating the interplay. Through reviewing the related research progress in the field, we hope to depict an integral overview of how OS induces depression, in order to provide fresh ideas and novel targets for the final goal of efficient treatment of the disease.

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Inhibition of IL-6 methylation by Saikosaponin C regulates neuroinflammation to alleviate depression

Cited by 12 publications

References 50 publications

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice

Mitochondrial antioxidant elamipretide improves learning and memory impairment induced by chronic sleep deprivation in mice

Associations between serum estradiol and IL-6/sIL-6R/sgp130 complex in female patients with major depressive disorder

How Oxidative Stress Induces Depression?

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