?-MSH related peptides: a new class of anti-inflammatory and immunomodulating drugs
2007
Abstract
alpha-Melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide derived from the proopiomelanocortin by post-translational processing. In addition to its effects on melanocytes, alpha-MSH has potent anti-inflammatory effects when administered systemically or locally. The anti-inflammatory effects of alpha-MSH are mediated by direct effects on cells of the immune system as well as indirectly by affecting the function of resident non-immune cells. alpha-MSH affects several pathways implicated in regulation of inflammatory responses such as NF-kappaB activation, expression of adhesion molecules and chemokine receptors, production of pro-inflammatory cytokines and other mediators. Thus alpha-MSH may modulate inflammatory cell proliferation, activity and migration. The anti-inflammatory effects of alpha-MSH have been confirmed by means of animal models of inflammation such as irritant and allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, ocular and brain inflammation. Most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tri-peptide KPV. K(D)PT, a derivative of KPV corresponding to the amino acid 193-195 of IL-1beta, is currently emerging as another tripeptide with potent anti-inflammatory effects. The anti-inflammatory potential together with the favourable physiochemical properties most likely will allow these agents to be developed for the treatment of inflammatory skin, eye and bowel diseases, allergic asthma and arthritis.
Conclusions
??MSH and related tripeptides have been shown to possess promising in vitro as well as in vivo anti?inflammatory effects. In particular the ??MSH?related tripeptides appear to be suited to being developed as anti?inflammatory drugs. Their small molecular size further provides advantages especially for local therapy of inflammatory diseases of skin and mucous membranes. Based on the combined anti?inflammatory and antimicrobial effects of some peptides, the risk for infection may be lower than with conventional immunosuppressive agents. Moreover, the broad anti?inflammatory effect will not result in strong immunosuppression as seen with the corticosteroids or systemic calcineurin inhibitors. Accordingly, activation of NF??B as well as subsequent expression of pro?inflammatory molecules is never fully suppressed, but mostly only reduced. In the absence of inflammation or pro?inflammatory stimuli such as LPS or IL1, the anti?inflammatory and immunosuppressive potential of ??MSH and its peptides was usually weak or absent. According to preliminary available toxicity and safety data, the adverse effects of ??MSH?related tripeptides seem to be minimal. Therefore, it is possible that ??MSH?related tripeptides will be developed as novel compounds for the treatment of immune?mediated inflammatory diseases.
The immunological milieu following tissue damage is complex, with a cascade of interacting mediators influencing the pathophysiological response. Although by no means as well defined as the evidence base supporting the role of melanocortin signaling in energy homeostasis, data now indicate that melanocortins can inhibit peripheral production of the chemical mediators of inflammation and, by doing so, potentially modify inflammatory cell migration. Interestingly, just as peripheral signals of energy balance are integrated within the brain, so do central melanocortinergic systems also appear to have an important role in modulating the inflammatory response to peripheral stress.
Melanocortins have long been known to have potent antipyretic properties, quite distinct from any role in normal thermoregulation and via a mechanism that does not involve the adrenal gland. Both -MSH and ACTH administered centrally can significantly ameliorate the fever brought on by peripheral administration of endogenous pyrogens even in adrenalectomized animals.
Direct action of -MSH on macrophages and fibroblasts can greatly reduce the production of proinflammatory cytokines and chemokines. Furthermore, a single intracerebroventricular injection of 10 µg -MSH in mice also receiving 200 mg Escherichia coli endotoxin intraperitoneally has been reported to change the outcome from all mice dying to 45% of the mice surviving.
Preliminary data also suggest that melanocortins may be able to influence outcome after hemorrhagic shock. ACTH and -MSH analogs have been reported to increase survival rates in rat models of hypovolemic shock, with 1 small case series describing a beneficial effect of ACTH given to patients with shock resulting from type A aortic dissection. However, there are no clear data to determine how much of this effect is independent of steroid production from the adrenals.
Common to both septic and hemorrhagic shock is the triggering of an inflammatory cascade characterized by increased production of cytokines like tumor necrosis factor-, chemokines, oxygen free radicals, and other inflammatory mediators. Melanocortins may be able to modulate this circulating inflammatory milieu via a neuronal effector arm arising from within the central nervous system. Thus, this antishock effect can be seen with intracerebroventricular doses much lower than those required by the intravenous route, with pharmacological or physical interruption of vagal outflow negating the effect. This cholinergic antiinflammatory pathway has been further explored by Gaurini et al, who combined precise anatomic perturbations with pharmacological interventions to show that in rats systemically shocked by hemorrhage, ACTH 1-24 can act through central MC4-R to trigger a vagal antiinflammatory pathway, inhibit nuclear factor-B activation, and reduce both hepatic tumor necrosis factor- mRNA content and tumor necrosis factor- plasma levels. More recently, peripheral administration of 2 novel melanocortin agonists, highly selective at MC4-R, has proved efficacious in a rat model of hemorrhagic shock, significantly reducing multiple organ damage and improving survival.
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