Retracted: Vagus Nerve Mediates the Protective Effects of Melanocortins against Cerebral and Systemic Damage after Ischemic Stroke

Abstract

A vagus nerve-mediated, efferent cholinergic protective pathway activated by melanocortins is operative in circulatory shock and myocardial ischemia. Moreover, melanocortins have neuroprotective effects against brain damage after ischemic stroke. Here we investigated cerebral and systemic pathophysiologic reactions to focal cerebral ischemia in rats induced by intrastriatal microinjection of endothelin-1, and the possible protective role of the melanocortin-activated vagal cholinergic pathway. In the striatum and liver of saline-treated control rats, the activation of extracellular signal-regulated kinases, c-jun N-terminal kinases, and caspase-3, the increase in tumor necrosis factor-a (TNF-a) concentration and DNA fragmentation, as well as the increase in TNF-a plasma levels, occurred 10 and 20 h after the ischemic insult suggesting an activation of inflammatory and apoptotic responses. Treatment with [Nle 4 , D-Phe 7 ]a-melanocyte-stimulating hormone (NDP-a-MSH; 3 or 9 h after stroke) suppressed the inflammatory and apoptotic cascades at central and peripheral level. Bilateral vagotomy and pharmacologic blockade of peripheral nicotinic acetylcholine receptors blunted the protective effect of NDP-a-MSH. The present results show that focal brain ischemia in rats causes significant effects not only in the brain, but also in the liver. Moreover, our data support the hypothesis that a protective, melanocortin-activated, vagal cholinergic pathway is likely operative in conditions of ischemic stroke.

Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery

“…Thus, our data suggest that cerebral ischemia enhances the parasympathetic tone. A recent study demonstrated that the vagus nerve mediates the anti-inflammatory and neuroprotective effect of a melanocortin derivative after cerebral ischemia (Ottani et al, 2008). Thus, the enhanced parasympathetic tone supported by our data may indicate an endogenous neuroprotective process.…”

Melanocortin-4 receptor agonists alleviate intestinal dysfunction in secondary intra-abdominal hypertension rat model

“…These endogenous peptides and their synthetic analogs play roles in protecting the body against various diseases, such as hemorrhagic shock, intestinal ischemia, ischemic stroke, and traumatic brain injury [10e12]. Previous studies have shown that the melanocortin-4 (MC4) receptor can play an antishock role via the vagus nervemediated cholinergic pathway [11,13] in a self-defense antiinflammatory mechanism that activates (as the main final step) the a7-acetylcholine receptor subunit on inflammatory cells [13,14].…”

Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS)

“…There are several other potential VNS clinical applications, reasoning from the known role of the vagus, including obesity (Roslin and Kurian, 2001), craving (Bodenlos et al, 2007), pain (Borckardt et al, 2006a(Borckardt et al, , 2005, traumatic brain injury (Colombo et al, 2008;Neese et al, 2007;Ottani et al, 2009), and anxiety (George et al, 2008b). These small sample size trials all suggest potential efficacies in these domains but RCT are needed.…”

“…There is also intense recent work investigating the role that VNS might have on inflammation and the immune response (Ottani et al, 2009;Pavlov, 2008;Van Der Zanden et al, 2009). …”