L-F001, a novel multifunctional ROCK inhibitor, suppresses neuroinflammation in vitro and in vivo: Involvement of NF-κB inhibition and Nrf2 pathway activation

Chen, Jingkao; Yin, Wei; Tu, Yalin; Wang, Shengnan; Yang, Xiaohong; Chen, Qiuhe; Zhang, Xiao; Han, Yifan; Pi, Rongbiao

doi:10.1016/j.ejphar.2017.03.025

Cited by 44 publications

(34 citation statements)

References 40 publications

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“…Transcription factors are proteins that bind to dna and regulate the transcriptional activity of genes. nF-κB, members of the STaT family, nuclear factor erythroid 2-related factor 2 (nrf2) and PParγ are 4 important transcription factors that have been associated with the mechanisms underlying microglia polarization (16,19,26,62,63) (Fig. 2).…”

Section: Modulatory Mechanisms Of Microglia Polarizationmentioning

confidence: 99%

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Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. as the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. in response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti-inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. it has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. in addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified. Contents 1. introduction 2. Microglia 3. Modulatory mechanisms of microglia polarization 4. autophagy 5. conclusions

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Section: Modulatory Mechanisms Of Microglia Polarizationmentioning

confidence: 99%

“…2). The first 2 transcription factors are closely associated with M1 polarization (16,19,62), whereas the other 2 are associated with M2 polarization (26,63).…”

Section: Modulatory Mechanisms Of Microglia Polarizationmentioning

confidence: 99%

Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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“…RhoA is involved in the proinflammatory cascades and was reported to be activated in the brain areas with focal cerebral infarction [12]. Emerging evidence supports that RhoA-ROCK signaling inhibition can alleviate the neuroinflammation and post-ischemic neuronal damages [2]. Moreover, previous study has highlighted the importance of SC in anti-inflammatory effect under cardiac hypertrophy through inactivating the calcineurin-NFAT2 pathway, a downstream cascade of RhoA-ROCK signaling pathway [19,24].…”

Section: Discussionmentioning

confidence: 97%

Sanggenon C Ameliorates Cerebral Ischemia-Reperfusion Injury by Inhibiting Inflammation and Oxidative Stress through Regulating RhoA-ROCK Signaling

Zhao

2020

Inflammation

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Sanggenon C (SC), a natural flavonoid extracted from Cortex Mori (Sang Bai Pi), is reported to possess anti-inflammatory and antioxidant properties in hypoxia. The present study aimed to investigate the therapeutic potential and the underlying mechanisms of SC in cerebral ischemia-reperfusion (I/R) injury. A rat model of reversible middle cerebral artery occlusion (MCAO) was used to induce cerebral I/R injury in vivo, and SC was administrated intragastrically. Brain injuries were evaluated using Bederson scores, brain water content, and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The levels of inflammatory factors and oxidative stress were examined using corresponding kits. Cell apoptosis was evaluated by TUNEL. Moreover, the expressions of apoptosis-related and RhoA/ROCK signaling-related proteins were detected through western blotting. In vitro, RhoA was overexpressed in oxygenglucose deprivation and reperfusion (OGD/R)-induced PC12 cells to confirm the contribution of RhoA-ROCK signaling inhibition by SC to the neuroprotective effects post OGD/R. Pretreatment with SC significantly ameliorated the neurologic impairment, brain edema, and cerebral infarction post MCAO-reperfusion, associated with reductions of inflammation, oxidative stress, and cell apoptosis in the brain. Furthermore, SC remarkably downregulated the expression of RhoA/ROCK signaling-related proteins post MCAO-reperfusion in rats, while overexpression of RhoA reversed the beneficial effects of SC on protecting against inflammation and oxidative stress in OGD/R-induced PC12 cells. Taken together, these findings demonstrated that SC exerts neuroprotective effects after cerebral I/R injury via inhibiting inflammation and oxidative stress through regulating RhoA-ROCK signaling, suggesting a therapeutic potential of SC in cerebral I/R injury.

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“…For example, cell culture studies have demonstrated that NQO1 and HO-1 overexpression in neuronal cells decreases oxidative damage following exposure to amyloid βor glutamate. consequently, microglia from HO-1 and NQO1-overexpressing transgenic mice are more resistant to lipopolysaccharide (LPS)-mediated and oxidative injury (14).…”

Section: Petasites Japonicus Bakkenolide B Inhibits Lipopolysaccharidmentioning

confidence: 99%

Petasites japonicus bakkenolide B inhibits lipopolysaccharide‑induced pro‑inflammatory cytokines via AMPK/Nrf2 induction in microglia

et al. 2017

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Abnormal neuroinflammatory responses have diverse roles in neuronal death, oxidative stress and neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Microglia regulate these responses via molecular signaling cascades that involve inflammatory cytokines and complement proteins. Bakkenolide B from Petasites japonicus exhibits significant anti‑inflammatory and anti‑allergic bioactivities. The present study investigated the anti‑neuroinflammatory effects and underlying molecular mechanisms of bakkenolide B on the lipopolysaccharide (LPS)‑mediated neuroinflammatory response in microglia. The results indicated that bakkenolide B pretreatment significantly reduced microglial production of interleukin (IL)‑1β, IL‑6, IL‑12, and tumor necrosis factor (TNF)‑α. Furthermore, this effect was associated with reduced production of reactive oxygen species. The role of bakkenolide B was then evaluated in the upregulation of nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathways. The results suggested that bakkenolide B significantly upregulated Nrf2/ARE pathway‑related downstream factors, such as NADPH dehydrogenase quinone‑1 (NQO‑1) and heme oxygenase‑1 (HO‑1). Silencing of Nrf2, HO‑1 and NQO‑1 diminished the anti‑neuroinflammatory properties of bakkenolide B. AMP‑activated protein kinase (AMPK) activates the Nrf2/ARE signaling pathway, and the results of the present study demonstrated that bakkenolide B increased AMPK phosphorylation in microglia. In addition, an AMPK inhibitor abolished the bakkenolide B‑induced increase in nuclear Nrf2, NQO‑1 and HO‑1 protein expression. Finally, an AMPK inhibitor diminished the bakkenolide B‑mediated inhibition of LPS‑stimulated TNF‑α production. Taken together, the present results demonstrate that bakkenolide B may be an effective and therapeutically relevant AMPK/Nrf2 pathway activator for suppressing abnormal neuro-inflammation in neurodegenerative diseases.

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L-F001, a novel multifunctional ROCK inhibitor, suppresses neuroinflammation in vitro and in vivo: Involvement of NF-κB inhibition and Nrf2 pathway activation

Cited by 44 publications

References 40 publications

Modulators of microglia activation and polarization in ischemic stroke (Review)

Modulators of microglia activation and polarization in ischemic stroke (Review)

Sanggenon C Ameliorates Cerebral Ischemia-Reperfusion Injury by Inhibiting Inflammation and Oxidative Stress through Regulating RhoA-ROCK Signaling

Petasites japonicus bakkenolide B inhibits lipopolysaccharide‑induced pro‑inflammatory cytokines via AMPK/Nrf2 induction in microglia

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