Toll-Like Receptor 4 Antagonist Attenuates Intracerebral Hemorrhage–Induced Brain Injury

Abstract Background Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. Methods We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. Results TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. Conclusions We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

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Forsythiaside-A Alleviates Traumatic Brain Injury by Regulating Toll-Like Receptor 4/Myeloid Differentiation Factor 88/Nuclear Factor-Kappa B Signaling Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:326-332 ◽

2021 ◽

Vol 19 (3) ◽

pp. 326-332

Author(s):

Jinsi Tian ◽

Xiaoya Xu ◽

Da Tian

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Signaling Pathway ◽

Brain Tissue ◽

Nuclear Factor Kappa B ◽

Myeloid Differentiation ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Myeloid Differentiation Factor

Traumatic brain injury refers to brain injury caused by mechanical impact often leading to severe morbidity and mortality. Despite increasing awareness, there are no effective treatments strategies. Therefore, there is a need to develop new effective treatments for this injury. Forsythiaside A is a monomer of phenylethanolglucoside extracted from Forsythia, which has a wide range of pharmacological properties including protective effects on brain tissue. Herein, using a rat model of traumatic brain injury, we have shown that forsythiaside A can improve nerve function and brain tissue injury in rats with traumatic brain injury, and reduce brain inflammation and neuronal apoptosis. We have further shown that forsythiaside A regulates toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B signaling pathway. This opens the possibility of a potentially promising therapeutic drug for the treatment of traumatic brain injury.

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Deep Succinylproteomics of Brain Tissues of Intracerebral Hemorrhage with Inhibition of Toll-like Receptor 4 Signaling

10.21203/rs.3.rs-392813/v1 ◽

2021 ◽

Author(s):

Yan-Jing Liang ◽

Yuan-Rui Yang ◽

Chuan-Yuan Tao ◽

Su-Hao Yang ◽

Xin-Xiao Zhang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Acid Metabolism ◽

High Resolution Mass Spectrometry ◽

Membrane Vesicle ◽

Transcriptome Data ◽

Toll Like Receptor ◽

Brain Protein ◽

Toll Like Receptor 4 ◽

Proteomics Approach ◽

Induced Changes

Abstract The details of Toll-like receptor (TLR) 4 signaling affects protein succinylation in intracerebral hemorrhage (ICH) brains remains completely unclear. In this study, we constructed mice ICH models to investigate the changes in ICH-associated brain protein succinylation with the treatment of TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized a concentration of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase in 29 succinyllysine sites of 28 succinylated proteins and reduction of 24 succinyllysine sites on 23 succinylated proteins in ICH brains. Both the TAK242 treatment induced hypersuccinylated and hyposuccinylated proteins in ICH brains were mainly located in mitochondria and cytoplasm. GO analysis showed that TAK242 treatment induced changes in ICH-associated succinylated proteins were mostly located in synapse, membrane, vesicle, etc., and enriched in many processes, such as metabolism, synapse, myeline, etc.. KEGG analysis showed that TAK242 induced downregulation of succinylation was significantly linked to fatty acid metabolism and lysosome. Moreover, a combination analysis of our succinylproteomic data with previously published transcriptome data identified that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed into neurons, astrocytes and endothelial cells; and 7 and 3 of these succinylated proteins significantly high express in neurons and astrocytes, respectively. In conclusion, our analyses uncover a number of TLR4 signaling affected succinylation processes and pathways in mouse ICH brains and provide new insights for understanding ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622.

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Propofol Ameliorates Ischemic Brain Injury by Blocking Toll-like Receptor 4-dependent Pathway and Suppressing Consequent Inflammatory Cytokine Production

10.21203/rs.3.rs-49562/v1 ◽

2020 ◽

Author(s):

Kazuha Mitsui ◽

Masakazu Kotoda ◽

Sohei Hishiyama ◽

Ayasa Takamino ◽

Sho Morikawa ◽

...

Keyword(s):

Brain Injury ◽

Inflammatory Cytokine ◽

Neuroprotective Effect ◽

Ischemic Brain Injury ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Neuroprotective Effects ◽

Inflammatory Cytokine Production ◽

Ischemic Brain ◽

Dependent Pathway

Abstract BackgroundIschemic stroke is one of the leading causes of mortality and morbidity worldwide. Accumulated evidence suggests that the consequent excessive inflammation plays detrimental roles in the pathogenesis of secondary injury after cerebral infarction and exacerbates the brain tissue damage. Although regulation of the inflammation would be the potential strategy for the novel treatment option, effective methods that control the cerebral inflammation have not yet been established. Recent studies have suggested that propofol, a sedative agent widely used for management of patients with acute stroke, suppresses excessive inflammation and may have neuroprotective effects against ischemic brain injury. However, the available evidence is still limited and controversial, and the underlying mechanism remains unclear. This study aimed to investigate the neuroprotective effects of propofol against ischemic brain injury, with a specific focus on Toll-like receptor 4 (TLR4), the critical mediator of inflammation in the ischemic brain.ResultsTreatment with propofol significantly reduced infarct volume in wild-type mice (7.9 ± 1.4 vs. 12.6 ± 1.1 mm3, n = 10 each, p < 0.05). The propofol-treated mice exhibited lower levels of pro-inflammatory cytokine expressions compared with the control mice (IL-6: 0.57 ± 0.23 vs. 1.00 ± 0.39, p < 0.05, IL-1β: 0.53 ± 0.24 vs. 1.00 ± 0.36, p = 0.087, n = 15 each). The neuroprotective effect of propofol was abrogated by TLR4 gene knockout. Propofol treatment had no significant effects on hemodynamic parameters.ConclusionsPropofol attenuates brain injury by blocking the TLR4-dependent pathway and suppressing pro-inflammatory cytokine production. This insight into the mechanism underlying the neuroprotective effect of propofol against ischemic brain injury may lead to a new strategy for preventing exacerbation of cerebral infarction.

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