GTS-21 Protected Against LPS-Induced Sepsis Myocardial Injury in Mice Through α7nAChR.

Abstract

Sepsis-induced myocardial injury is a well-known cause of mortality. The cholinergic anti-inflammatory pathway (CHAIP) is a physiological mechanism by which the central nervous system regulates immune response through the vagus nerve and acetylcholine; the α7-nicotinic acetylcholine receptor (α7nAChR) is the main component of CHAIP; GTS-21, a synthetic α7nAChR selective agonist, has repeatedly shown its powerful anti-inflammatory effect. However, little is known about its effect on LPS-induced myocardial injury. We investigated the protective effects of GTS-21 on lipopolysaccharide (LPS)-induced cardiomyopathy via the cholinergic anti-inflammatory pathway in a mouse sepsis model. We constructed the model of myocardial injury in sepsis mice by C57BL/6 using LPS and determined the time of LPS treatment by hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). C57BL/6 mice were randomized into five groups: blank control group, model group, α-bungarotoxin + LPS group, GTS-21 + LPS group, and α-bungarotoxin + GTS-21 + LPS group. The pathological results of myocardial tissue were detected by the HE method; the apoptosis rate was detected by the TUNEL method; the relative expressions of NF-κB p65, Caspase-3, Caspase-8, Bcl-2, Bax, p53, and a7nAChR were detected by real-time quantitative PCR (RT-PCR); and the protein expressions of IL-6, IL-1 β, TNF-α, and pSTAT3 were detected by western blot. The results showed that LPS-induced myocardial pathological and apoptosis changes were significant compared with the blank group, which was reversed by GTS-21; however, pretreatment with α-bungarotoxin obviously blocked the protective effect of GTS-21. NF-κB p65, Caspase-3, Caspase-8, Bax, p53, IL-6, IL-1β, TNF-α, and pSTAT3 were significantly increased in the model group, while a7nAChR and Bcl-2 were significantly decreased; GTS-21 treatment reversed that result, while pretreatment with α-bungarotoxin strengthened the result in the model. And pretreatment with α-bungarotoxin blocked the protective effect of GTS-21. GTS-21 can alleviate the LPS-induced damage in the heart via a7nAChR, and pretreatment with α-bungarotoxin obviously blocked the protective effect of GTS-21 on sepsis in mice.

• Authors: Weilan Kong, Kai Kang, Yang Gao, Haitao Liu, Xianglin Meng, Yanhui Cao, Songliu Yang, Wen Liu, Jiannan Zhang, Kaijiang Yu, Mingyan Zhao
• Journal: Inflammation (Inflammation) Vol. 41 Issue 3 Pg. 1073-1083 (Jun 2018) ISSN: 1573-2576 [Electronic] United States
• PMID: 29680908 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Benzylidene Compounds
• Bungarotoxins
• Lipopolysaccharides
• Pyridines
• alpha7 Nicotinic Acetylcholine Receptor
• 3-(2,4-dimethoxybenzylidene)anabaseine

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Apoptosis (drug effects)
• Benzylidene Compounds (pharmacology)
• Bungarotoxins (pharmacology)
• Heart Injuries (chemically induced)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Pyridines (pharmacology)
• Sepsis (drug therapy)
• alpha7 Nicotinic Acetylcholine Receptor (agonists, analysis, antagonists & inhibitors)