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The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling

  • Jing-Jing Du
  • Zhi-Qin Liu
  • Yue Yan
  • Jing Xiong
  • Xiao-Tao Jia
  • Zheng-Li Di
  • Jing-Jing RenEmail author
Article

Abstract

Delayed neurologic sequelae (DNS) are among the most serious complications of carbon monoxide (CO) poisoning caused partly by elevated neuroinflammation. WIN 55,212-2, a non-selective agonist of cannabinoid receptors, has been demonstrated to have anti-inflammatory properties in various brain disorders. The anti-inflammatory action of WIN 55,212-2 is potentially associated with driving microglial M2 polarization. ST2 signaling is important in regulating inflammatory responses and microglial polarization. Therefore, we aimed to investigate the neuroprotective effect of WIN 55,212-2 on DNS after CO poisoning and elucidate its relationship with ST2-mediated microglial M2 polarization. The behavioral tests showed that treatment with WIN 55,212-2 significantly ameliorates the cognitive impairment induced by CO poisoning. This behavioral improvement was accompanied by reduced neuron loss, decreased production of pro-inflammatory cytokines, and a limited number of microglia in the hippocampus. Moreover, WIN 55,212-2 elevated the protein expression of IL-33 (the ligand of ST2) and ST2, increased the ratio of CD206-positive (M2 phenotype) and ST2-positive microglia, and augmented production of M2 microglia-associated cytokines in the hippocampus of CO-exposed rats. Furthermore, we observed that the WIN 55,212-2-mediated increases in ST2 protein expression, CD206-positive and ST2-positive microglia, and microglia-associated cytokines were blocked by the cannabinoid receptor 2 (CB2R) antagonist AM630 but not by the cannabinoid receptor 1 (CB1R) antagonist AM251. In contrast, the WIN 55,212-2-induced upregulation of the IL-33 protein expression was inhibited by AM251 but not by AM630. Altogether, these findings reveal cannabinoid receptors as promising therapeutic agents for CO poisoning and identify ST2 signaling-related microglial M2 polarization as a new mechanism of cannabinoid-induced neuroprotection.

Keywords

Carbon monoxide poisoning WIN 55,212-2 Microglia ST2 Neuroinflammation 

Abbreviations

2-AG

2-Arachidonoylglycerol

AEA

Anandamide

CB1R

Cannabinoid type 1 receptor

CB2R

Cannabinoid type 2 receptor

CO

Carbon monoxide

DNS

Delayed neurologic sequelae

ECL

Enhanced chemiluminescence

IL-10

Interleukin-10

IL-1β

Interleukin-1β

IL-33

Interleukin-33

IL-4

Interleukin-4

LPS

Lipopolysaccharide

MWM

Morris water maze

NO

Nitric oxide

ROS

Reactive oxygen species

SD

Standard deviation

TNF-α

Tumor necrosis factor-α

TUNEL

Terminal deoxytransferase-mediated dUTP nick end labeling

WIN

WIN 55,212-2

Notes

Funding Information

This work was supported by a grant from the National Natural Science Foundation of China (grant number 81501139.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.Department of Neurology, Xi’an Central HospitalXi’an Jiaotong UniversityXi’anChina
  2. 2.Department of Hematology, Xi’an Central HospitalXi’an Jiaotong UniversityXi’anChina

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