Alpha-7 nicotinic acetylcholine receptor agonist GTS-21 influences the inflammatory response in an animal model of heart failure

Abstract

Abstract Cardiovascular disease, specifically heart failure affects nearly 6 million Americans, and remains to be the number one cause of hospitalization and death globally. Multiple studies have suggested that inflammation plays a pivotal role in the pathogenesis of this disease. There is a novel link between the vagus nerve and the inflammatory responses, where the vagus nerve can limit inflammation via the alpha-7 nicotinic acetylcholine receptor (α7 nAChR) in relation to the “cholinergic anti-inflammatory pathway (CAP)”. Selective pharmacological stimulation of the α7 nAChR may have therapeutic potential for the treatment of inflammatory conditions. We determined the anti-inflammatory potential of 3-(2,4-dimethoxybenzylident)-anabaseine (GTS-21), an α7-selective partial agonist, in an in vivo zebrafish heart failure model. To investigate the possible therapeutic benefit of GTS- 21, we used a chronic exposure system in which animals are pre-treated with GTS-21 for 20 minutes per day for four consecutive days. On day four after a short washout period, heart failure is chemically induced by Oligo-[2-(2- ethoxy)-ethoxyethyl)-guanidinium-chloride] (PGH) and survival is recorded. We show that GTS-21 has a profound anti-inflammatory effect in improving survivability in a concentration dependent manner. Moreover, rtPCR analysis on heart tissue shows that pre-treatment with GTS-21 induces modifications in levels of gene regulatory proteins leading to altered cytokine expression within the myocardium. In all, these data indicate that GTS-21 may be a promising therapeutic as it influences the inflammatory response in heart failure.