Alpha7 cholinergic-agonist prevents systemic inflammation and improves survival during resuscitation.
Severe haemorrhage is a common cause of death despite the recent advances in critical care. Conventional resuscitation fluids are designed to re-establish tissue perfusion, but they fail to prevent inflammatory responses during resuscitation. Our previous studies indicated that the vagus nerve can modulate systemic inflammation via the alpha7 nicotinic acetylcholine receptor (alpha7nAchR). Here, we report that the alpha7nAChR-agonist, GTS, restrains systemic inflammation and improves survival during resuscitation. Resuscitation with GTS rescued all the animals from lethal haemorrhage in a concentration-dependent manner. Unlike conventional resuscitation fluids, GTS inhibited the production of characteristic inflammatory and cardiodepressant factors including tumour necrosis factor (TNF) and high mobility group B protein-1 (HMGB1). Resuscitation with GTS was particularly effective in restraining systemic TNF responses and inhibiting its production in the spleen. At the molecular level, GTS inhibited p65RelA but not RelB NF-kappaB during resuscitation. Unlike non-specific nicotinic agonists, GTS inhibited serum protein TNF levels in both normal and splenectomized, haemorrhagic animals. Resuscitation with GTS inhibited poly(ADP-ribose) polymerase and systemic HMGB1 levels. Our studies suggest that GTS provides significant advantages as compared with non-specific nicotinic agonists, and it could be a promising anti-inflammatory supplement to improve survival during resuscitation.
Cai
Bolin
B
Laboratory of Anti-inflammatory Signaling and Surgical Immunology, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Chen
Fei
F
Ji
Yan
Y
Kiss
Levente
L
de Jonge
Wouter J
WJ
Conejero-Goldberg
Concepcion
C
Szabo
Csaba
C
Deitch
Edwin A
EA
Ulloa
Luis
L
D000818:Animals; D001597:Benzylidene Compounds / Q000627:therapeutic use*; D018679:Cholinergic Agonists / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000378:metabolism; D007249:Inflammation; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012151:Resuscitation; D013154:Spleen / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D018679:Cholinergic Agonists; C579165:Chrna7 protein, rat; D024243:HMGB1 Protein; D016328:NF-kappa B; D011725:Pyridines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D011065:Poly(ADP-ribose) Polymerases