Melanocortins: anti-inflammatory and neuroprotective peptides

C. CARUSO; L. CARNIGLIA; D. DURAND; M. LASAGA

Neurodegeneration

InTech

Lugar: Rijeka; Año: 2012; p. 93 - 120

The melanocortins, a, b, and g-melanocyte stimulating hormones (MSH) and adrenocorticotrophin, are neuropeptides that derive from pro-opiomelanocortin cleavage. They are synthesized in several tissues, mainly in the pituitary gland and the central nervous system (CNS). The melanocortin system has two endogenous antagonists: agouti,expressed in the skin, and agouti-related peptide, expressed in the hypothalamus, which counteract melanocortin actions. This system is involved in pigmentation, energy homeostasis, endocrine and exocrine gland secretion, regulation of sexual behaviour, immunomodulation and neuroprotection. Over the past two decades five melanocortin receptors (MCRs) have been cloned and some insight into their function has been gained. MCRs show distinct expression patterns, MC3R and MC4R being expressed mainly in the brain. Specifically, MC3R and MC4R are expressed in several neuronal areas such as hypothalamus, hippocampus and thalamus. MC3R is involved in energy homeostasis and is proposed to function as an autoreceptor in neurons, although it is not involved in neuroprotection. MC4R regulates food intake and energy expenditure, stimulates neurite elongation and mediates neuroprotective, anti-pyretic, and anti-inflammatory effects of melanocortins. Recent studies from our laboratory determined that MC4R is the only subtype expressed in non-neuronal cells, i.e. astrocytes. Anti-inflammatory effects: Inflammation is a physiological response to infection or tissue injury in order to restore homeostasis. Cytokines (like IL-1b and TNF-alpha), chemokines, nitric oxide and prostaglandins are some of the mediators of inflammatory processes that induce vasodilatation and extravasation of neutrophils into injured tissue. In several models of inflammatory disease, melanocortins decrease the release of several of these mediators and also the infiltration of neutrophils into the site of injury. The acute inflammatory response usually terminates once the insult is eliminated and tissue repaired. If this does not occur inflammation becomes chronic, leading to harmful effects. Ideal anti-inflammatory agents should reduce an exacerbated immune response but not eliminate it. Anti-inflammatory actions of melanocortins in peripheral organs are well known and reduce excessive inflammation. Therefore, melanocortins are good candidates for treatment of inflammatory diseases. However, in view of the variety of effects produced by these neuropeptides, it is necessary to develop more selective and potent agonists for each receptor to avoid undesired side effects. Melanocortin anti-inflammatory action in the brain is less extensively studied but includes: reduction of fever induced by lipopolysaccharide or cytokines (IL-1b, TNF-a), reduction of cytokine (IL-1b, TNF-a) release induced by cerebral ischemia or brain inflammation models and reduced production of nitric oxide and prostaglandins induced by IL-1b in rat hypothalamus. We showed that MC4R-mediated effects include decreasing nitric oxide and prostaglandin release as well as expression of their synthesizing enzymes in hypothalamus of male rats and in rat astrocytes. Melanocortins can also have anti-inflammatory effects in neurons as well, since an inflammatory stimulus increases the expression of TNF-a in hypothalamic neurons and melanocortins decrease this effect. However, mechanisms of action of melanocortins are still unclear. They seem to involve modulation of cytokine production by decreasing activation of the nuclear factor-kB (NF-kB). Although this is true for immune peripheral cells, contrasting reports show that melanocortins do not inhibit NF-kB activation induced by pro-inflammatory stimulus.  Neuroprotective effects: A common feature of neurodegenerative diseases is chronic immune activation in the brain. Cytokines have a dual role in inflammation and disease. They contribute to the acute phase of inflammation but are also able to have protective roles in later stages of injury. Similar action is shown in neurodegeneration: given that IL-1b and TNF-a are increased in neurodegenerative diseases such as Parkinson s disease, Alzheimer s disease and multiple sclerosis, they are believed to be involved in the etiology of these pathologies. However, the role of inflammation in the development of neurodegenerative disorders is not clear. A general understanding indicates that inflammatory processes contribute to the onset of neurodegenerative diseases. If this is the case, modulation of inflammation provides an opening to new treatment approaches in acute and chronic disease of the CNS. Also, since local inflammation leads to recovery and regeneration, reduction rather than abolishment of inflammatory response is the best option. Melanocortins are prime candidates for this task. Locally or systemically administered melanocortins induce nerve regeneration. A melanocortin analogue also protects hippocampal neurons from dying after cerebral ischemia in gerbils, and after excitotoxicity. We described that MC4R activation protects astrocytes from apoptosis induced by an inflammatory stimulus and it was also shown that it protects hypothalamic neurons from serum deprived-induced apoptosis. Mechanisms of action are not completely understood but seem to involve increased expression of anti-apoptotic protein Bcl-2 and also reduction of nitric oxide. Ligand binding to MCRs activated adenylate cyclase which led to production of cAMP and subsequent activation of cAMP response element-binding protein (CREB). alpha-MSH activates CREB in the hypothalamic paraventricular nucleus, in cultured hypothalamic neurons and astrocytes. CREB is responsible for cell survival during metabolic or oxidative stress and can modulate Bcl-2 expression. Thus, CREB could be mediating melanocortin anti-inflammatory and antiapoptotic actions. The mitogen activated protein kinase ERK is also activated by all melanocortin receptors and could contribute to melanocortin effects as well. Chronic inflammation influences the pathogenesis and progression of Parkinson s disease, Alzheimer s disease and multiple sclerosis. Although there is no evidence of melanocortin effects on models of Parkinson s disease, anti-inflammatory therapies such as nonsteroidal anti-inflammatory drugs (NSAIDs) were neuroprotective. However, for Alzheimer s disease the use of NSAIDs aggravated or had no effect on the disease. Thus, melanocortins could be a better approach to treating these disorders, since they regulate but do not eliminate inflammatory response. It is possible that they could preserve the benefits of inflammatory response without its harmful effects. In fact, alpha-MSH was suggested to be useful in the treatment of inflammatory experimental autoimmune encephalomyelitis, a T-cell mediated inflammatory autoimmune process that resembles the human demyelinating disease multiple sclerosis. Orally administered alpha-MSH can reduce signs of the disease and inhibit CNS inflammation. Self-reactive T cells with alpha-MSH may represent a clinically viable approach to treat autoimmune diseases. Brain-derived neurotrophic factor (BDNF) has proved to be neuroprotective in Alzheimer s disease, multiple sclerosis and Parkinson s disease. We recently demonstrated that MC4R activation in cultured astrocytes induces expression of BDNF, also shown for hypothalamic explants by others, suggesting that BDNF could be a mediator of melanocortin action in the brain. It is likely that melanocortins can induce neuroprotective genes such as Bcl-2 and BDNF, thereby contributing to ameliorate neurodegenerative diseases. However, much study is needed to prove this hypothesis.In summary, melanocortins have great potential for treatment of neurodegenerative diseases because of their potent anti-inflammatory, neurotrophic and neuroprotective effects in the CNS.