Title

 

Authors

S. Guarini¹, A. Ottani¹, M. Galantucci¹, L. Spaccapelo¹, D. Zaffe², D.Giuliani¹
 
Dept. of Biomedical Sciences, Sections of ¹Pharmacology and ²Human Morphology, University of Modena and Reggio Emilia, Italy 

 

Abstract

The identification of drugs able to activate the “cholinergic anti-inflammatory pathway” (1,2) might provide highly effective and innovative approaches for the treatment of circulatory shock. Melanocortin peptides of the ACTH/MSH group have a prompt and sustained resuscitating effect in conditions of circulatory shock. This effect is adrenal-independent, and seemingly occurs through a counteraction of the systemic inflammatory response. Action potential recordings have shown that, in hemorrhage-shocked rats intravenously treated with a nanomolar dose of ACTH-(1-24), neural efferent activity along vagus nerve markedly increases, and this effect is associated with the restoration of cardiovascular and respiratory functions, blunted NF-kB activity and decreased TNF-α mRNA liver content and TNF-α plasma levels. Moreover, bilateral cervical vagotomy, or pharmacological blockade of brain melanocortin MC₄ receptors and muscarinic acetylcholine receptors, or of peripheral nicotinic acetylcholine receptors, prevents the life-saving effect of ACTH-(1-24) and the associated effects on NF-kB activity and TNF-α levels.The blockade of brain MC₄ receptors and muscarinic receptors also a) blunts the stimulating effect of ACTH-(1-24) on efferent vagal activity, b) reduces, like bilateral cervical vagotomy, the blood volume to be withdrawn in order to induce shock, and c) prevents the compensatory increase in efferent vagal activity normally occurring during bleeding in control shocked animals. Together, these findings indicate that melanocortins activate the cholinergic anti-inflammatory pathway (3). Evidence also indicates that this pathway might be melanocortin-dependent.
Electrical stimulation of the vagus nerve has been reported to prevent ventricular fibrillation and ventricular tachycardia in cats and rats after myocardial reperfusion, to reduce infarct size in rats, and to prevent ventricular fibrillation in dogs with a healed myocardial infarction. Moreover, it has been reported that vagus stimulation improves long-term survival after chronic heart failure in rats.These observations stimulated investigations aimed at determining whether melanocortin peptides activate such vagal efferent pathway(s) in experimental conditions of ischemic heart disease. Nanomolar amounts of the melanocortins ACTH-(1-24) (agonist at all MC receptors) and γ₂-MSH (selective agonist at MC₃ receptors) – administered in rats during coronary occlusion intravenously, or intracerebroventricularly at a dose 10 times lower – produces the same protective effects of efferent vagal fibre electrical stimulation (4). Accordingly, bilateral cervical vagotomy blunts the beneficial effect of ACTH-(1-24) and of the selective MC₃ agonist γ₂-MSH, and blockade of peripheral muscarinic acetylcholine receptors prevents the effects of both electrical stimulation and melanocortins. The protective effect of melanocortins, therefore, likely involves the cholinergic anti-inflammatory pathway.The melanococortin-induced activation of such a pathway seems to be triggered by stimulation of brain MC₃ receptors,with involvement of brain and (as main final step) heart muscarinic receptors.
Overall, these results point to the identification of a protective, efferent vagal cholinergic pathway operative in conditions of circulatory shock and ischemic heart disease (5), that could be activated by melanocortins. These findings could have major clinical implications.

1. Tracey (2002).Nature. 420:853-859.
2. Guarini et al. (2003). Circulation. 107:1189-1194.
3. Guarini et al. (2004). Cardiovasc Res. 63:357-365.
4. Mioni et al. (2005). Crit Care Med.33:2621-2628.
5. Giuliani et al. (2010). Adv Exp Med Biol.681:71-87