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Resolvin D1 Attenuates Innate Immune Reactions in Experimental Subarachnoid Hemorrhage Rat Model

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Abstract

Excessive inflammation is a major cause contributing to early brain injury (EBI) and is associated with negative or catastrophic outcomes of subarachnoid hemorrhage (SAH). Resolvin D1 (RvD1) exerts strong anti-inflammatory and pro-resolving effects on either acute or chronic inflammation of various origin. Henceforth, we hypothesized that RvD1 potentially attenuates excessive inflammation in EBI following SAH. Therefore, we generated a filament perforation SAH model and administered 3 different doses (0.3, 0.6, and 1.2 nmol) of RvD1 after experimental SAH. Neurological scores, brain edema, and blood–brain barrier integrity were evaluated; besides, neutrophil infiltration, neuronal deaths, and microglial pro-inflammatory polarization were observed using histopathology or immunofluorescence staining, western blots, and qPCR. After confirming the effectiveness of RvD1 in SAH, we administered the FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4) 30 min before SAH establishment to observe whether this compound could abolish the anti-inflammatory effect of RvD1. Altogether, our results showed that RvD1 exerted a strong anti-inflammatory effect and markedly reduced neutrophil infiltration and microglial pro-inflammatory activation, leading to remarkable improvements in neurological function and brain tissue restoration. After addition of WRW4, the anti-inflammatory effects of RvD1 were abolished. These results indicated that RvD1 could exert a good anti-inflammatory effect and alleviate EBI, which suggested that RvD1 might be a novel therapeutic alternative for SAH-induced injury.

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Data Availability

The datasets supporting the conclusions of this article are included within the article (and its additional file).

Abbreviations

RvD1:

Resolvin D1

SAH:

Subarachnoid hemorrhage

EBI:

Early brain injury

i.c.v. :

Intracerebroventricular

FPR2:

Formyl peptide receptor 2

WRW4:

Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRWWWW)

IL-1β:

Interleukin 1 beta

TNF-α:

Tumor necrosis factor alpha

NLRP3:

NLR family pyrin domain containing 3

iNOS:

Induced nitric oxide synthases

MPO:

Myeloperoxidase

ICAM-1:

Intercellular adhesion molecule 1

CINC-1:

Cytokine-induced neutrophil chemoattractant 1

CXCL-2:

C-X-C motif chemokine 2

MCP-1:

Monocyte chemotactic protein 1

IBA-1:

Ionized calcium binding adaptor molecule-1

GFAP:

Glial fibrillary acidic protein

DHA:

Docosahexaenoic acid

H&E:

Hematoxylin-eosin staining

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

TRAF6:

TNF receptor associated factor 6

RRIDs:

Research resource identifiers

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Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC): No. 81870922 (Wei Li); No. 81771291 (Chun-Hua Hang); Medical Science and Technology Development Foundation, Nanjing Department of Health: No. JQX18001 (Wei Li); and the Fundamental Research Funds for the Central Universities No. 021414380361 (Wei Li).

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G-J L is responsible for study design, performing experiments, manuscript drafting; TT analyses and interprets of results; X-S Z is responsible for animal management and drug administration; YL and L-Y W are responsible for statistical analysis; Y-Y G and HW are responsible for cell culture; H-B D is responsible for immunofluorescence staining; YZ is responsible for neurological evaluation; ZZ is responsible for primary reversion of manuscript; C-H H is responsible for study design; WL is responsible for study design and critical revision of manuscript; all authors read and approved the final manuscript.

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Correspondence to Chun-Hua Hang or Wei Li.

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Liu, GJ., Tao, T., Zhang, XS. et al. Resolvin D1 Attenuates Innate Immune Reactions in Experimental Subarachnoid Hemorrhage Rat Model. Mol Neurobiol 58, 1963–1977 (2021). https://doi.org/10.1007/s12035-020-02237-1

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