Post-stroke DHA Treatment Protects Against Acute Ischemic Brain Injury by Skewing Macrophage Polarity Toward the M2 Phenotype

Systemic docosahexaenoic acid (DHA) has been explored as a clinically feasible protectant in stroke models. However, the mechanism for DHA-afforded neuroprotection remains elusive. Transient middle cerebral artery occlusion (tMCAO) was induced for 1 h. DHA (i.p., 10 mg/kg) was administered immediate...

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Bibliographic Details
Published in:Translational stroke research 2018-12, Vol.9 (6), p.669-680
Main Authors: Cai, Wei, Liu, Sanxin, Hu, Mengyan, Sun, Xiaobo, Qiu, Wei, Zheng, Songguo, Hu, Xiaoming, Lu, Zhengqi
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Antibodies
Biomedical and Life Sciences
Biomedicine
Blood
Brain Injuries - drug therapy
Brain Injuries - etiology
Brain Injuries - pathology
Brain Ischemia - complications
Cardiology
Carotid arteries
Cell Polarity - drug effects
Cytokines - genetics
Cytokines - metabolism
Disease Models, Animal
Docosahexaenoic Acids - therapeutic use
Female
Flow Cytometry
Genotype & phenotype
In Situ Nick-End Labeling
Inflammation
Ischemia
Laboratory animals
Macrophages - drug effects
Macrophages - pathology
Male
Mice
Mice, Inbred C57BL
Microglia - drug effects
Microglia - pathology
Nervous System Diseases - drug therapy
Nervous System Diseases - etiology
Neurology
Neuroprotective Agents - therapeutic use
Neurosciences
Neurosurgery
Neutrophil Infiltration - drug effects
Original Article
Protein Array Analysis
RNA, Messenger - metabolism
Spleen
Stroke
Time Factors
Traumatic brain injury
Vascular Surgery
Veins & arteries
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Summary:Systemic docosahexaenoic acid (DHA) has been explored as a clinically feasible protectant in stroke models. However, the mechanism for DHA-afforded neuroprotection remains elusive. Transient middle cerebral artery occlusion (tMCAO) was induced for 1 h. DHA (i.p., 10 mg/kg) was administered immediately after reperfusion and repeated daily for 3 days. Stroke outcomes, systemic inflammatory status, and microglia/macrophage phenotypic alterations were assessed 3 days after stroke. Macrophage depletion was induced by clodronate liposomes injection. Primary macrophage cultures were used to evaluate the direct effect of DHA on macrophages. We demonstrated that post-stroke DHA injection efficiently reduced brain infarct and ameliorated neurological deficits 3 days after tMCAO. Systemic DHA treatment significantly inhibited immune cell infiltration (macrophages, neutrophils, T lymphocytes, and B lymphocytes) and promoted macrophage polarization toward an anti-inflammatory M2 phenotype in the ischemic brain. Meanwhile, systemic DHA administration inhibited the otherwise elevated pro-inflammatory factors in blood and shifted circulating macrophage polarity toward M2 phenotype after ischemic stroke. The numbers of circulating immune cells in blood and spleen, however, were equivalent between DHA- and vehicle-treated groups. The protective effects of DHA were macrophage-dependent, as macrophage depletion abolished DHA-afforded neuroprotection. In vitro studies confirmed that DHA suppressed production of chemokines and pro-inflammatory cytokines from macrophages under inflammatory stimulation. These data indicate that post-stroke DHA treatment ameliorated acute ischemic brain injury in a macrophage-dependent manner and DHA enhanced macrophage phenotypic shift toward an anti-inflammatory phenotype to reduced central and peripheral inflammation after stroke.
ISSN:1868-4483
1868-601X
DOI:10.1007/s12975-018-0662-7