The neuroprotective effect of phillyrin in intracerebral hemorrhagic mice is produced by activation of the Nrf2 signaling pathway

Guo, Xin; Cao, Pingping; Lian, Xiongfeng; Hu, Meng; Zhao, Jinfang; Shen, Wenjing; Wang, Haili; Yu, Hailong; Chen, Yingzhu

doi:10.1016/j.ejphar.2021.174439

Cited by 16 publications

(8 citation statements)

References 32 publications

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“…Phi restrained H 2 O 2 exposure–induced oxidative stress in PC12 cells ( Wei et al, 2014 ). Most recently, intraperitoneal injection of Phi ameliorates neurological deficits and lesion volume by improved apoptosis and oxidative stress in intracerebral hemorrhagic mice by activating the Nrf2/HO-1 pathway ( Guo et al, 2021 ). Our previous study had confirmed the neuroprotective effects of Phi against TBI ( Jiang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization

Jiang

Ding

et al. 2021

Front. Pharmacol.

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Background: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood–brain barrier (BBB) damage following traumatic brain injury (TBI) remains unknown.Materials and Methods: Lipopolysaccharide (LPS) was used to activate primary microglia, which were then treated with different doses of Phi or the peroxisome proliferator–activated receptor-gamma (PPARγ) antagonist (GW9662). CCK-8 assay was used for evaluating cell viability, and the cytokines (including IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ), microglial phenotypic markers (iNOS, COX2, and CD86 for “M1” polarization; Arg1, Ym1, and CD206 for “M2” polarization), PPARγ, and NF-κB were determined by RT-PCR, Western blot, or cellular immunofluorescence. Primary cultured mouse brain microvascular endothelial cells (BMECs) were stimulated by the condition medium (CM) from microglia. The cell viability, angiogenesis, and tight junction of BMECs were determined via CCK-8 assay, tube formation assay, and Western blot (for detecting MMP3, MMP9, ZO1, claudin-5, and occludin). Furthermore, the mouse TBI model was constructed and treated with Phi and/or GW9662. The BBB integrity was evaluated by H&E staining, Evans blue staining, and tissue immunofluorescence.Results: Phi markedly restrained the pro-inflammatory (“M1” state) cytokines and promoted anti-inflammatory (“M2” polarization) cytokines in LPS-mediated microglia. Phi mitigated “M1” polarization and promoted “M2” polarization of microglia via enhancing PPARγ and inhibiting the NF-κB pathway. The PPARγ antagonist GW9662 significantly repressed Phi-mediated anti-inflammatory effects. Meanwhile, Phi enhanced the viability, tube formation ability, and cell junction of BMECs. In the TBI mouse model, Phi promoted “M2” polarization, whereas it repressed the “M1” polarization of microglia. In addition, Phi reduced TBI-mediated BBB damage. However, the protective effects of Phi were reversed mainly by GW9662 treatment.Conclusion: Phi prevents BBB damage via inhibiting the neuroinflammation of microglia through the PPARγ/NF-κB pathway, which provides a potential therapeutic drug against TBI.

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Section: Discussionmentioning

confidence: 99%

Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization

Jiang

Ding

et al. 2021

Front. Pharmacol.

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“…Modern pharmacology is not deep enough to study phillyrin, although some studies have shown that phillyrin has the effects of antioxidation and anticancer [ 149 ]. Phillyrin increased the expression of Nrf2, HO-1, NQO1, and SOD-1, and decreased the expression of MDA and ROS in the in vitro and in vivo ICH model [ 89 ].…”

Section: Targeted Therapy Of Oxidative Stress With Natural Productsmentioning

confidence: 99%

Targeting Oxidative Stress in Intracerebral Hemorrhage: Prospects of the Natural Products Approach

Zheng

Fan

2022

Antioxidants

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Intracerebral hemorrhage (ICH), the second most common subtype of stroke, remains a significant cause of morbidity and mortality worldwide. The pathological mechanism of ICH is very complex, and it has been demonstrated that oxidative stress (OS) plays an important role in the pathogenesis of ICH. Previous studies have shown that OS is a therapeutic target after ICH, and antioxidants have also achieved some benefits in the treatment of ICH. This review aimed to explore the promise of natural products therapy to target OS in ICH. We searched PubMed using the keywords “oxidative stress in intracerebral hemorrhage” and “natural products in intracerebral hemorrhage.” Numerous animal and cell studies on ICH have demonstrated the potent antioxidant properties of natural products, including polyphenols and phenolic compounds, terpenoids, alkaloids, etc. In summary, natural products such as antioxidants offer the possibility of treatment of OS after ICH. However, researchers still have a long way to go to apply these natural products for the treatment of ICH more widely in the clinic.

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“…Previous studies showed that phillyrin protects against oxidative stress damage by activating the Nrf2 signaling pathway. Recently, it was found that phillyrin is neuroprotective in ICH via its activation of the Nrf2 signaling pathway ( Guo et al, 2021 ). Phillyrin significantly reduced lesion volume, improved the white and gray matter injury around the lesion, decreased apoptosis and oxidative stress, increased the expression of Nrf2, HO-1, NQO1, and SOD-1 in in vitro and in vivo models, and protected neurons from hemin stimulation by promoting Nrf2 nuclear translocation ( Guo et al, 2021 ).…”

Section: Therapeutic Potential Of Nuclear Factor Erythroid-2-related ...mentioning

confidence: 99%

Regulation of nuclear factor erythroid-2-related factor 2 as a potential therapeutic target in intracerebral hemorrhage

Zhang

Liu

et al. 2022

Front. Mol. Neurosci.

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Hemorrhagic stroke can be categorized into several subtypes. The most common is intracerebral hemorrhage (ICH), which exhibits significant morbidity and mortality, affecting the lives of millions of people worldwide every year. Brain injury after ICH includes the primary injury that results from direct compression as well as stimulation by the hematoma and secondary brain injury (SBI) that is due to ischemia and hypoxia in the penumbra around the hematoma. A number of recent studies have analyzed the mechanisms producing the oxidative stress and inflammation that develop following hematoma formation and are associated with the ICH induced by the SBI as well as the resulting neurological dysfunction. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a critical component in mediating oxidative stress and anti-inflammatory response. We summarize the pathological mechanisms of ICH focusing on oxidative stress and the regulatory role of Nrf2, and review the mechanisms regulating Nrf2 at the transcriptional and post-transcriptional levels by influencing gene expression levels, protein stability, subcellular localization, and synergistic effects with other transcription factors. We further reviewing the efficacy of several Nrf2 activators in the treatment of ICH in experimental ICH models. Activation of Nrf2 might produce antioxidant, anti-inflammatory, and neuron-protection effects, which could potentially be a focus for developing future treatments and prevention of ICH.

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The neuroprotective effect of phillyrin in intracerebral hemorrhagic mice is produced by activation of the Nrf2 signaling pathway

Cited by 16 publications

References 32 publications

Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization

Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization

Targeting Oxidative Stress in Intracerebral Hemorrhage: Prospects of the Natural Products Approach

Regulation of nuclear factor erythroid-2-related factor 2 as a potential therapeutic target in intracerebral hemorrhage

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