Melanocortins and the Cholinergic Anti-Inflammatory Pathway

Abstract

Experimental evidence indicates that small concentrations of inflammatory molecules produced by damaged tissues activate afferent signals through ascending vagus nerve fibers, that act as the sensory arm of an "inflammatory reflex". The subsequent activation of vagal efferent fibers, which represent the motor arm of the inflammatory reflex, rapidly leads to acetylcholine release in organs of the reticuloendothelial system. Acetylcholine interacts with α7 subunit-containing nicotinic receptors in tissue macrophages and other immune cells and rapidly inhibits the synthesis/release of tumor necrosis factor-α and other inflammatory cytokines. This neural anti-inflammatory response called "cholinergic anti-inflammatory pathway" is fast and integrated through the central nervous system. Preclinical studies are in progress, with the aim to develop therapeutic agents able to activate the cholinergic anti-inflammatory pathway. Melanocortin peptides bearing the adrenocorticotropin/α-melanocyte-stimulating hormone sequences exert a protective and life-saving effect in animals and humans in conditions of circulatory shock. These neuropeptides are likewise protective in other severe hypoxic conditions, such as prolonged respiratory arrest, myocardial ischemia, renal ischemia and ischemic stroke, as well as in experimental heart transplantation. Moreover, experimental evidence indicates that melanocortins reverse circulatory shock, prevent myocardial ischemia/reperfusion damage and exert neuroprotection against ischemic stroke through activation of the cholinergic anti-inflammatory pathway. This action occurs via stimulation of brain melanocortin MC3/MC4 receptors. Investigations that determine the molecular mechanisms of the cholinergic anti-inflammatory pathway activation could help design of superselective activators of this pathway.

Some Aspects of the Normal Role of Neuromodulators in the Immune System

“…The subsequent activation of vagal efferent fibers, which represent the motor arm of the inflammatory reflex, rapidly leads to acetylcholine release in organs of the reticuloendothelial system, including the spleen, liver, and gastrointestinal tract. Here acetylcholine interacts with α7 subunitcontaining nicotinic receptors in tissue macrophages and other immune cells, which inhibits NF-kappaB nuclear translocation and rapidly inhibits the synthesis/release of tumor necrosis factor-α and other inflammatory cytokines by monocytes and macrophages [45][46][47][48]. Monocytes have alpha7 nicotinic acetylcholine receptors that inhibit the production of proinflamatory cytokines by suppression of IkB phosphorylation and nuclear factor-kB transcriptional activity [49].…”

Adrenocorticotropic hormone versus methylprednisolone added to interferon β in patients with multiple sclerosis experiencing breakthrough disease: a randomized, rater-blinded trial

“…Orally administered ACTH exerts anti-inflammatory effects in mice via modulation of regulatory T (Treg) cells [Szabo et al 1989]. Both ACTH 1-39 and ACTH 1-24 activate anti-inflammatory signals by potentiating sympathetic/adrenergic pathways [Gothert, 1984;Brzoska et al 2008], which play a role in the efferent anti-inflammatory cholinergic pathway [Giuliani et al 2010]. Neurotrophic effects were suggested in spinal cord injury and protective effects in ischemic brain injury [Catania et al 2004;Gong, 2011].…”

Molecular Changes Induced in Rat Liver by Hemorrhage and Effects of Melanocortin Treatment

“…Through an efferent vagal pathway, central melanocortins protected rats against myocardial ischemia/reperfusion injury, ischemic stroke, and hemorrhagic shock. 16,44 Further, research on acute inflammation in the mouse indicated that ␣-melanocyte-stimulating hormone can act solely within the brain to inhibit nuclear factor-B activation in peripheral tissues. 43,44 This latter effect appeared to be mediated by sympathetic signals that require a peripheral ␤ 2 adrenergic receptor.…”

“…17,18 Conversely, the short half-life of peptide molecules, including natural melanocortins, that are broken down readily in the body fluids, should not represent a limitation as several of the generated fragments are biologically active. 10 Finally, passage through the blood-brain barrier 10,12,44,45 and lack of receptor selectivity of melanocortins should not be problematic in short-term, acute treatments such as in hemorrhagic shock.…”

“…Central neurogenic antiinflammatory signals activated by melanocortins consist of both adrenergic 42,43 and cholinergic 16,44 pathways. It appears that these central modulatory effects depend on activation of MC 4 receptors within the brain.…”