Trends in Pharmacological Sciences
ReviewTargeting the melanocortin receptor system for anti-stroke therapy
Introduction
Stroke is a leading cause of death worldwide and the most common cause of permanent adult disability. Despite this, current treatments remain wholly inadequate. As of 2006, a total of 7554 results from 1082 prospective neuroprotective interventions had been published on the treatment of stroke 1, 2; however, translation to the clinic has been extremely disappointing (Table 1). Intravenous administration of clot-busting tissue plasminogen activator (tPA) remains the only practised treatment for acute ischaemic stroke. However a restricted 3-h therapeutic window and risk of intracerebral haemorrhage associated with its use indicate an urgent need for more efficient stroke therapies.
Inflammation following an ischaemic period is increasingly being seen as a major contributing factor to the pathogenesis of stroke. A detrimental inflammatory response provides potential therapeutic targets and extends the therapeutic window. Potent anti-inflammatory and neuroregenerative actions have been attributed to circuits centred on the melanocortins and their receptors. The melanocortin receptor system thus provides a particularly attractive target for the development of novel therapeutics for stroke. In this review, the role of the inflammatory system in stroke is discussed, along with the animal models currently used to assess potential therapies. The biology of melanocortin receptors is reviewed and current efforts to use them as anti-stroke treatments is explored.
Section snippets
Epidemiology and aetiology of cerebrovascular accidents
Cerebral diseases are highly prevalent in populations that are increasingly disposed to pathological risk factors such as hypertension, obesity and smoking. Cerebrovascular accidents (CVAs) – including ischaemic and haemorrhagic stroke – are a leading cause of death, second only to heart disease worldwide [1] and third behind heart disease and cancer in England and Wales [2]. Moreover, high-quality palliative care is essential for CVA survivors; with a survival rate of 76%, stroke is currently
The melanocortin system
Research into melanocortin peptides has revealed a multitude of effects on numerous physiological functions in the host, ranging from regulation of skin pigmentation to energy metabolism and memory formation, as well as neuroprotection and inflammation 11, 12. Thus, the melanocortin system is rapidly being acknowledged as an extremely promising target for pharmacological intervention in a wide variety of conditions, including stroke.
The melanocortin peptides comprise adrenocorticotrophic
Concluding remarks
There is wide appreciation of the important involvement of inflammation in the pathogenesis of a plethora of diseases, including stroke. The resolution of inflammation and its importance in anti-stroke therapy has been highlighted in this review. The melanocortin system might provide an attractive target for stroke therapy, not only because of its potent anti-inflammatory, pro-resolving actions, but also because of its neuroprotective, neurotrophic and anti-pyretic effects. Further detailed
Acknowledgements
F.N.E.G. and H.K.S. are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and P.H. is supported by a British Heart Foundation studentship. S.G., F.R.J. and M.P. are funded by the Higher Education Funding Council of England.
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Cited by (27)
Multiple beneficial effects of melanocortin MC<inf>4</inf> receptor agonists in experimental neurodegenerative disorders: Therapeutic perspectives
2017, Progress in NeurobiologyCitation Excerpt :Consistently, preconditioning and postconditioning as innovative strategies against ischemia/reperfusion injury of several organs including the brain — and against other CNS insults — are under investigation, with encouraging results (Granfeldt et al., 2009; Stetler et al., 2014; Veighey and Macallister, 2012). Moreover, the antipyretic action of melanocortins is well established, and melanocortin-induced hypothermia can likewise contribute to neuroprotection against acute neurodegeneration (Holloway et al., 2011; Spulber et al., 2005; Tatro, 2006; Tatro and Sinha, 2003). Experimental and clinical studies provide increasing evidence that therapeutic hypothermia could be useful in several brain injuries (Marion and Bullock, 2009; Maybhate et al., 2012; Moore et al., 2011; Salerian and Saleri, 2008; Yenari and Han, 2012).
NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC<inf>4</inf> receptors
2015, Molecular and Cellular NeuroscienceMelanocortin peptides protect chondrocytes from mechanically induced cartilage injury
2014, Biochemical PharmacologyCitation Excerpt :Nevertheless, this initial viewpoint is currently changing [32,64]. Melanocortin peptides are derived from the larger, pre-cursor pro-opiomelanocortin (POMC) protein [65,66] and exert their effects via the activation of melanocortin receptors/adenylate cyclase/cAMP signalling pathway [65]. Although five melanocortin receptors (MC) have been identified, all positively coupled to adenylate cyclase via Gs and activate cAMP pathways, the anti-inflammatory effect of melanocortin peptides has been found to be mediated primarily via MC1, MC3 and MC5 [65,66].
Resolution of inflammation: Examples of peptidergic players and pathways
2014, Drug Discovery TodayCitation Excerpt :α-MSH and NDP-MSH have potent immune-modulating properties, and inhibit many inflammatory responses including myocardial ischemia, whereby the neuropeptides reduced inflammatory and apoptotic pathways, and induced antiapoptotic reactions [23]. α-MSH, NDP-MSH and the selective MC4 receptor small molecule agonist RO27-3225 can counteract the inflammatory and apoptotic responses resulting from cerebral ischemia, improving neuronal function by inducing neurogenesis and long-lasting functional recovery [24]. In models of allergic lung inflammation, α-MSH and [DTRP8]-γ-MSH inhibit eosinophil and leukocyte accumulation, whereas in non-allergic models neutrophil accumulation and tumour necrosis factor (TNF)-α production were abridged [25], an effect largely mediated by MC3.
α-Melanocyte-stimulating hormone inhibits angiogenesis through attenuation of VEGF/VEGFR2 signaling pathway
2014, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Moreover, we further delineated the involvement of MC1-R and MC2-R, but not MC4-R and MC5-R, in the anti-angiogenic mechanism of α-MSH in endothelial cells. Given that α-MSH preferentially binds to MC1-R over MC4-R or MC5-R [38], it seemed reasonable to exclude MC4-R and MC5-R from α-MSH-mediating signaling in endothelial cells. Nevertheless, the role of MC2-R in transmitting α-MSH signaling is intriguing because MC2-R binds only ACTH and has no affinity for the other melanocortin peptides [39].
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Joint first authors.