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.
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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
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This work was supported by a grant from the National Natural Science Foundation of China (grant number 81501139.
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Du, JJ., Liu, ZQ., Yan, Y. et al. The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling. J Mol Neurosci 70, 422–432 (2020). https://doi.org/10.1007/s12031-019-01429-2
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DOI: https://doi.org/10.1007/s12031-019-01429-2