Propofol reduces microglia activation and neurotoxicity through inhibition of extracellular vesicle release

Liu, Jianhui; Li, Yuju; Xia, Xiaohuan; Yang, Xiaoyu; Zhao, Runze; Peer, Justin; Wang, Hongyun; Tong, Zenghan; Fengtong, Gao; Lin, Hai; Wu, Beiqing; Huang, Yunlong; Zheng, Jialin

doi:10.1016/j.jneuroim.2019.05.003

Cited by 19 publications

(12 citation statements)

References 41 publications

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“…Propofol, as one of the most commonly used IV drugs for the anesthesia induction and maintenance during surgical procedures and critical care sedation in ICUs, has been reported to have potential therapeutic effects on various neurological disorders including neurodegenerative diseases (Shao et al, 2014), stroke (Hausburg et al, 2020), and depression (Mickey et al, 2018). Here, our results, together with our previous study (Liu et al, 2019), have demonstrated the anti-inflammatory roles of propofol in both microglial cell line and primary microglia. Our findings match with the results obtained from various in vitro and in vivo studies, implying propofol as a promising drug candidate in treating neuroinflammation and its related diseases (Peng et al, 2014;Liu et al, 2017;Luo et al, 2018;Wu Q. et al, 2018;Zheng et al, 2018).…”

Section: Discussionsupporting

confidence: 79%

“…Propofol acts by potentiating the γ-aminobutyric acid type A (GABA A ) receptormediated inhibitory tone in the CNS (Marik, 2004). Interestingly, our group, together with other labs, have reported that propofol is able to modulate the phenotype of BV2 microglial cells and assert anti-inflammatory effects (Luo et al, 2018;Wu Q. et al, 2018;Zheng et al, 2018;Liu et al, 2019). Similar results were obtained when primary microglia were treated with propofol (Peng et al, 2014).…”

Section: Introductionsupporting

confidence: 68%

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Propofol Inhibits Microglial Activation via miR-106b/Pi3k/Akt Axis

Liu

Sun

et al. 2021

Front. Cell. Neurosci.

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Propofol is an established intravenous anesthetic agent with potential neuroprotective effects. In this study, we investigated the roles and the underlying mechanisms of propofol in inhibiting the pro-inflammatory responses of microglia. Propofol significantly reduced the messenger RNA (mRNA) levels of Tnf, Nos2, and NF-κB pathway related genes Ticam1, Myd88, Irf3, and Nfkb1 in lipopolysaccharide (LPS)-treated primary microglia. After screening the miRNA profiles in microglia under LPS and propofol treatment conditions, we found propofol abrogated the LPS-induced misexpression of miRNAs including miR-106b, miR-124, miR-185, and miR-9. Perturbation of function approaches suggested miR-106b as the core miRNA that mediated the anti-inflammatory effects of propofol on microglial activation. RNA sequencing (RNA-seq) analysis further identified Pi3k/Akt signaling as one of the most affected pathways after miR-106b perturbation of function. The treatment of Pi3k/Akt signaling agonist 740Y-P elevated miR-106b-reduced Akt phosphorylation and abolished the inhibitory effects of miR-106b on the pro-inflammatory responses of microglia. Our results suggest propofol inhibits microglial activation via miR-106b/Pi3k/Akt axis, shedding light on a novel molecular mechanism of propofol-mediated immunomodulatory effects and implying propofol as potential therapeutics for treating neuroinflammation-related neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionsupporting

confidence: 68%

Propofol Inhibits Microglial Activation via miR-106b/Pi3k/Akt Axis

Liu

Sun

et al. 2021

Front. Cell. Neurosci.

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“…Yu et al [ 6 ] revealed that propofol inhibited the microglial phagocytosis under increase pressure circumstance. In addition, Liu and his colleagues found that propofol can suppress microglial activity, including phagocytosis ability, in response to lipopolysaccharide (LPS) exposure [ 9 ]. However, there is currently limited evidence regarding the effect of a single administration of propofol on resting microglia, i.e., in the absence of activation-inducing insult.…”

Section: Discussionmentioning

confidence: 99%

“…Propofol, a widely used short-acting intravenous sedative agent used in clinical practice, is often selected for general anesthesia or sedation of patients receiving surgery or undergoing diagnostic procedures [ 7 ]. Evidence has indicated that propofol can attenuate microglial responses when cells are exposed to external stimuli [ 8 , 9 ]. It can inhibit pressure-stimulated macrophage phagocytosis via the GABA A receptor [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Propofol suppresses microglial phagocytosis through the downregulation of MFG-E8

Cai

Liu

Zheng

et al. 2021

J Neuroinflammation

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Background Microglia are highly motile phagocytic cells in the healthy brain with surveillance and clearance functions. Although microglia have been shown to engulf cellular debris following brain insult, less is known about their phagocytic function in the absence of injury. Propofol can inhibit microglial activity, including phagocytosis. Milk fat globule epidermal growth factor 8 (MFG-E8), as a regulator of microglia, plays an essential role in the phagocytic process. However, whether MFG-E8 affects the alteration of phagocytosis by propofol remains unknown. Methods Microglial BV2 cells were treated with propofol, with or without MFG-E8. Phagocytosis of latex beads was evaluated by flow cytometry and immunofluorescence. MFG-E8, p-AMPK, AMPK, p-Src, and Src levels were assessed by western blot analysis. Compound C (AMPK inhibitor) and dasatinib (Src inhibitor) were applied to determine the roles of AMPK and Src in microglial phagocytosis under propofol treatment. Results The phagocytic ability of microglia was significantly decreased after propofol treatment for 4 h (P < 0.05). MFG-E8 production was inhibited by propofol in a concentration- and time-dependent manner (P < 0.05). Preadministration of MFG-E8 dose-dependently (from 10 to 100 ng/ml) reversed the suppression of phagocytosis by propofol (P < 0.05). Furthermore, the decline in p-AMPK and p-Src levels induced by propofol intervention was reversed by MFG-E8 activation (P < 0.05). Administration of compound C (AMPK inhibitor) and dasatinib (Src inhibitor) to microglia blocked the trend of enhanced phagocytosis induced by MFG-E8 (P < 0.05). Conclusions These findings reveal the intermediate role of MFG-E8 between propofol and microglial phagocytic activity. Moreover, MFG-E8 may reverse the suppression of phagocytosis induced by propofol through the regulation of the AMPK and Src signaling pathways.

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“…Propofol induces the anti-inflammatory treatment by suppressing microglial activation after CA and TNF-α and IL-1β release, likely via the purinergic ligand-gated ion channel 7 receptor (P2X7R)/phosphor-p38 (p-p38) pathway [117]. Another study shows propofol might reduce microglia activation and neurotoxicity by inhibiting extracellular vesicle release [118]. These shreds of evidence suggest that propofol may be a new treatment for neuroinflammation after CA.…”

Section: Propofolmentioning

confidence: 99%

Inflammatory responses involved in post-cardiac arrest brain injury: mechanisms, regulation, and therapeutic potential

Zhang

et al. 2023

Explor Neurosci

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Neuroinflammation plays a key role in the pathogenesis of post-cardiac arrest (CA) brain injury. Innate immune cells sense a variety of danger signals through pattern-recognition receptors and evoke rapidly after ischemic challenge, triggering inflammatory responses and amplifying brain damage. A programmed cell death (PCD) pathway is activated after ischemic and/or inflammatory stimuli, leading to the elimination of the damaged cells. However, PCD also regulates inflammatory responses flexibly. The present review aimed to summarize the mechanisms of inflammatory responses, including the biology of immune cells, the innate immune recognition that initiates the inflammation, and the immunomodulatory effects of PCD following CA. Promising therapeutic approaches of targeting inflammatory responses to alleviate brain injury and improve neurological outcomes after CA are also reviewed.

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Propofol reduces microglia activation and neurotoxicity through inhibition of extracellular vesicle release

Cited by 19 publications

References 41 publications

Propofol Inhibits Microglial Activation via miR-106b/Pi3k/Akt Axis

Propofol Inhibits Microglial Activation via miR-106b/Pi3k/Akt Axis

Propofol suppresses microglial phagocytosis through the downregulation of MFG-E8

Inflammatory responses involved in post-cardiac arrest brain injury: mechanisms, regulation, and therapeutic potential

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