Neuroprotective Effect of Phthalide Derivative CD21 against Ischemic Brain Injury:Involvement of MSR1 Mediated DAMP peroxiredoxin1 Clearance and TLR4 Signaling Inhibition

Zhang, Xiao; Yang, Xi; Gan, Yu-Miao; Liu, Dongling; Chen, Chu; Duan, Wei; Du, Jun-Rong

doi:10.1007/s11481-020-09911-0

Cited by 24 publications

(16 citation statements)

References 37 publications

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“…Next, we examined the expression of V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) and MSR1 in the ipsilateral brain hemisphere, the function of which is to clear DAMPs (e.g., Prx1) after stroke [ 18 , 19 ]. Their expression was significantly upregulated by tPA after ischemia ( p < 0.05, vs. tMCAO group).…”

Section: Resultsmentioning

confidence: 99%

“…As a newly synthesized phthalide derivative, the anti-neuroinflammatory and neuroprotective effects of CD21 have been investigated in different rodent models of ischemic stroke. Our previous studies showed that CD21 might alleviate post-ischemia inflammation and brain injury in tMCAO rats and mice [ 19 , 26 , 27 ]. In the present study, we further explored the effect of CD21 on tPA-induced HT in tMCAO mice.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, Prx-based therapy is a potential strategy with a wide therapeutic window for post-stroke inflammation. Interestingly, emerging evidence suggests that DAMPs are internalized and cleared in the lysosome in a macrophage scavenger receptor 1 (MSR1)-dependent manner [ 18 , 19 ]. Neuroinflammation that is stimulated by DAMPs (e.g., HMGB1 and Prxs) after brain ischemia was shown to be negatively regulated by MSR1, which conferred potent neuroprotection within a 24-h therapeutic time window in mice that were subjected to transient middle cerebral artery occlusion (tMCAO) [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous study found that CD21 dose-dependently and significantly ameliorated neuroinflammation and brain injury in rodent models of ischemic stroke. Its neuroprotective mechanism of action was associated with the induction of microglial/macrophage M2 polarization and MSR1-promoted DAMP (Prx1)/TLR4/NF-κB pathway inhibition [ 19 , 26 , 27 ]. Based on these findings, the present study further explored the effects and underlying mechanism of action of CD21 on tPA-induced neurovascular complications in acute ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

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Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Liu

Hong

et al. 2021

J Neuroinflammation

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Background Hemorrhagic transformation (HT) is a critical issue in thrombolytic therapy in acute ischemic stroke. Damage-associated molecular pattern (DAMP)-stimulated sterile neuroinflammation plays a crucial role in the development of thrombolysis-associated HT. Our previous study showed that the phthalide derivative CD21 attenuated neuroinflammation and brain injury in rodent models of ischemic stroke. The present study explored the effects and underlying mechanism of action of CD21 on tissue plasminogen activator (tPA)-induced HT in a mouse model of transient middle cerebral artery occlusion (tMCAO) and cultured primary microglial cells. Methods The tMCAO model was induced by 2 h occlusion of the left middle cerebral artery with polylysine-coated sutures in wildtype (WT) mice and macrophage scavenger receptor 1 knockout (MSR1−/−) mice. At the onset of reperfusion, tPA (10 mg/kg) was intravenously administered within 30 min, followed by an intravenous injection of CD21 (13.79 mg/kg/day). Neuropathological changes were detected in mice 3 days after surgery. The effect of CD21 on phagocytosis of the DAMP peroxiredoxin 1 (Prx1) in lysosomes was observed in cultured primary microglial cells from brain tissues of WT and MSR1−/− mice. Results Seventy-two hours after brain ischemia, CD21 significantly attenuated neurobehavioral dysfunction and infarct volume. The tPA-infused group exhibited more severe brain dysfunction and hemorrhage. Compared with tPA alone, combined treatment with tPA and CD21 significantly attenuated ischemic brain injury and hemorrhage. Combined treatment significantly decreased Evans blue extravasation, matrix metalloproteinase 9 expression and activity, extracellular Prx1 content, proinflammatory cytokine mRNA levels, glial cells, and Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway activation and increased the expression of tight junction proteins (zonula occludens-1 and claudin-5), V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, and MSR1. MSR1 knockout significantly abolished the protective effect of CD21 against tPA-induced HT in tMCAO mice. Moreover, the CD21-induced phagocytosis of Prx1 was MSR1-dependent in cultured primary microglial cells from WT and MSR1−/− mice, respectively. Conclusion The phthalide derivative CD21 attenuated tPA-induced HT in acute ischemic stroke by promoting MSR1-induced DAMP (Prx1) clearance and inhibition of the TLR4/NF-κB pathway and neuroinflammation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Liu

Hong

et al. 2021

J Neuroinflammation

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“…1 Most patients who went through stroke do not benefit from the current therapies including thrombolysis and thrombectomy due to limited therapeutic time window and secondary brain injury. 2 Application of exogenous antioxidants has been demonstrated as beneficial against brain ischemic injury, but its efficacy remains unstable. Moreover, the detrimental connections between immune cells, glial cells, and matrix components during the pathology of stroke lead to inflammation that develops to fibrosis.…”

Section: Introductionmentioning

confidence: 99%

<p>NR4A2 Exacerbates Cerebral Ischemic Brain Injury via Modulating microRNA-652/Mul1 Pathway</p>

Liu¹,

Dong²

2020

NDT

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Background: Nuclear receptor subfamily group A member 2 (NR4A2), a transcription factor, was suggested to be involved in the pathogenesis of ischemic stroke. Nevertheless, the specific role of NR4A2 in ischemic brain injury has yet to be elucidated. Our aim was to probe the mechanisms behind the repression of microRNA (miRNA) expression resulting from NR4A2 regulation in ischemic brain injury. Methods: A rat model with transient global cerebral ischemia (tGCI) was established, followed by HE staining and immunohistochemistry for verification. Subsequently, NR4A2 expression in rat brain tissues was detected by RT-qPCR, Western blot and immunohistochemistry. Then, PC12 cells were treated with NR4A2 alteration and subjected to oxygenglucose deprivation (OGD) for cerebral ischemia simulation. Cell viability, apoptosis and cycle distribution were detected by CCK-8 and flow cytometry, respectively. miR-652 expression in rat brain tissues and cells was then detected by RT-qPCR, and then the targeting mRNAs of miR-652 were predicted through bioinformatic websites. Finally, the effect of miR-652 and mitochondrial E3 ubiquitin ligase 1 (Mul1) on the PC12 cell activity after OGD treatment was verified by rescue experiments. Results: NR4A2 and Mul1 were expressed highly in brain tissues of rats with tGCI, while miR-652 was expressed poorly. NR4A2 inhibited the expression of miR-652 by transcription, thus blocking the inhibition of miR-652 on Mul1 to repress PC12 cell activity and promote apoptosis and G0/G1 cell cycle arrest. Conclusion: The transcription factor NR4A2 mediates the expression of Mul1 through transcriptional repression of miR-652, thus promoting ischemic brain injury.

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Synthesis and Biological Evaluation of Novel Phthalide Analogs‐1,2,4‐Oxadiazole Hybrids as Potential Anti‐Inflammatory Agents

Ruan

Tang

Guo

et al. 2022

Chemistry & Biodiversity

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A series of novel pathalide-1,2,4-oxadiazole analogs were synthesized for discovering novel anti-inflammatory agents. After the assessment of their cytotoxicity in vitro, all compounds had been screened for their antiinflammatory activity by evaluating their inhibitory effect on LPS-induced NO production in RAW 264.7 macrophages. SARs had been concluded, and finally compound E13 was found to be the most potent compound. This compound could also significantly decrease the production of iNOS and COX-2. Preliminary mechanism studies indicated that compound E13 could inhibit the TLR4/NF-кB and ERK/p38 signaling pathways. These findings indicate that E13 holds great potential to be a lead compound for discovering novel antiinflammatory drugs.

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Neuroprotective Effect of Phthalide Derivative CD21 against Ischemic Brain Injury:Involvement of MSR1 Mediated DAMP peroxiredoxin1 Clearance and TLR4 Signaling Inhibition

Cited by 24 publications

References 37 publications

Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance

<p>NR4A2 Exacerbates Cerebral Ischemic Brain Injury via Modulating microRNA-652/Mul1 Pathway</p>

Synthesis and Biological Evaluation of Novel Phthalide Analogs‐1,2,4‐Oxadiazole Hybrids as Potential Anti‐Inflammatory Agents

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