File(s) under permanent embargo
Neuroprotective effect of phthalide derivative CD21 against ischemic brain injury:involvement of MSR1 mediated DAMP peroxiredoxin1 clearance and TLR4 signaling inhibition
journal contribution
posted on 2021-06-01, 00:00 authored by X Zou, Xing YangXing Yang, Y M Gan, D L Liu, C Chen, Wei DuanWei Duan, J R DuThe macrophage scavenger receptor 1 (MSR1)-induced resolution of neuroinflammation may be a novel therapeutic strategy for ischemic stroke. Our previous study showed that the neuroprotective and anti-inflammatory effects of phthalide are associated with the inhibition of the post-ischemic damage-associated molecular pattern (DAMP)/Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of the phthalide derivative CD21 on ischemic brain injury and the mechanism underlying MSR1-induced resolution of neuroinflammation. Using a rat model of 2 h transient middle cerebral artery occlusion (MCAO), MSR1-induced peroxiredoxin1 (PRX1) clearance in RAW264.7 macrophages were investigated. We show here that CD21 significantly ameliorated infarct volumes and neurological deficits in a dose-dependent manner with a ≥ 12 h therapeutic time window. Moreover, administration of 5 mg/kg/day CD21 over 24 h significantly reduced pathological damages, with associated inhibition of PRX1 expression, reduced TLR4/nuclear factor-κB activation and the suppression of the inflammatory response in MCAO rats. Furthermore, the expression of MAFB/MSR1 in the ischemic brain was elevated and the phagocytosis of PRX1 in CD68-positive macrophages isolated from the ischemic brain was enhanced. Further in vitro studies show that CD21 (20 μM) strongly enhanced the Msr1 mRNA and MSR1 protein levers in RAW264.7 cells and PRX1 internalization in cellular lysosomes, which were significantly reversed by N-acetylcysteine treatment. These results suggest that CD21 may exert neuroprotective and anti-inflammatory effects with a wide time window for the treatment of ischemic stroke. The anti-stroke effects of CD21 appear to be mediated partially via the induction of MSR1-promoted DAMP (PRX1) clearance, TLR4/nuclear factor-κB pathway inhibition, and the resolution of inflammation. [Figure not available: see fulltext.]
History
Journal
Journal of neuroimmune pharmacologyVolume
16Issue
2Pagination
306 - 317Publisher
SpringerLocation
New York, N.Y.Publisher DOI
ISSN
1557-1890eISSN
1557-1904Language
engPublication classification
C1 Refereed article in a scholarly journalUsage metrics
Categories
Keywords
Science & TechnologyLife Sciences & BiomedicineNeurosciencesPharmacology & PharmacyNeurosciences & NeurologyIschemic strokeNeuroinflammationMSR1DAMPs (peroxiredoxin1) internalizationTLR4\/NF-kappa B pathwayZ-LIGUSTILIDESCAVENGER RECEPTORSTROKE RESEARCHINJURYDAMAGEPATHOPHYSIOLOGYOVEREXPRESSIONINFLAMMATIONCONTRIBUTESMECHANISMSTLR4\/NF-κB pathwayImmunology
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC