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Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine Tufts-New England Medical Center and Tufts University School of Medicine Boston, Massachusetts 02111
Address all correspondence and requests for reprints to Jeffrey B. Tatro, Ph.D., Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Box 268, Tufts-New England Medical Center, and Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts 02111. E-mail: jtatro{at}tufts-nemc.org.
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Introduction |
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 Top Introduction Pathways of Destruction,...Melanocortins Protect the...Real or Illusory Promise...References |
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Pathways of Destruction, Frustrated Interventions |
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TopIntroductionPathways of Destruction,...Melanocortins Protect the...Real or Illusory Promise...References |
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B (NF-B), the latter cells and activated microglia release proinflammatory cytokines (e.g. TNF-
, IL1-ß) and synthesize inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), causing further toxic RNS and ROS accumulation. The death of neurons and other cells is thought to occur by three broad mechanisms: excitotoxicity, ionic imbalance, and apoptotic-like programmed cell death. The whole process evolves in a characteristic temporospatial pattern, wherein the ischemic core suffers the most severe insults and massive, rapid necrotic cell death, whereas in a more peripheral region, known as the penumbra, cells are exposed to less intense ischemia, but at risk of delayed death through inflammatory and programmed cell death pathways. Because it is generally impractical in the clinical setting to intervene early enough after stroke to save neurons in the ischemic core, the penumbra is the battleground for rescue of viable brain tissue and the focus of efforts to develop effective neuroprotective strategies, by targeting slowly developing processes such as inflammation and apoptosis (5, 6, 7). The discoveries of key mediators of ischemic neuronal cell death gave rise to a corresponding array of promising investigational therapeutic strategies. Unfortunately, so far not a single neuroprotective agent has survived clinical trials to yield an Food and Drug Administration-approved therapy. These discouraging results reflect the challenging nature of the therapeutic target, but also adverse side effects of the agents, and difficulties in the design and execution of clinical trials (1, 8)—factors that tend to deter aggressive pursuit of this therapeutic area by pharmaceutical firms despite the large and potentially lucrative market. Indeed, the main route of functional recovery from stroke relies on the brain’s awesome intrinsic adaptive powers and plasticity, involving recruitment and reorganization of undamaged motor circuitry (9), perhaps encouraged by rehabilitative and exercise therapies (10), and also generation of new neurons (11). There is strong consensus that outcomes may be improved by combining new or existing therapies to target multiple contributing cell types and pathogenic processes (1, 7, 8). Such targets are deployed throughout the neurovascular unit, a conceptual framework that encompasses leukocytes, endothelium, extracellular matrix, glia and neurons, and emphasizes the importance of their dynamic interactions in postischemic pathophysiology (5, 6).
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Melanocortins Protect the Postischemic Brain through Multiple Lines of Defense |
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TopIntroductionPathways of Destruction,...Melanocortins Protect the...Real or Illusory Promise...References |
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-MSH (NDP-MSH) reduced postischemic tissue injury and improved recovery of behavioral functions, even when treatment was begun up to 9 h after ischemia. There are five known MCR subtypes, common to humans and other mammals (designated MC1R through MC5R). The MC4R has been a focus of interest concerning its roles in controlling energy balance and is a potential target for new antiobesity drugs. In adult animals, it is principally expressed in the central nervous system (CNS), where it is the predominant known MCR subtype, and is expressed widely in neuroendocrine and autonomic centers as well as in basal ganglia, hippocampus, and cerebral cortex (12). The neuroprotective effects of NDP-MSH were prevented by a selective antagonist of MC4R (4), raising the possibility of targeting this multitalented receptor as a novel strategy for stroke pharmacotherapy. Peripheral melanocortin treatment markedly inhibited biochemical and histopathological markers of ischemia-induced tissue damage and neuronal loss in the CA1 subfield of hippocampus, a region important in spatial learning and memory that is particularly sensitive to ischemia-induced cell death (5). Markers of hippocampal apoptosis were reduced, as was activation of caspase-3, an apoptosis-mediating "executioner" enzyme, and of the stress-activated protein kinases c-Jun N-terminal kinase (JNK) and MAPK p38 (p38), thought to be involved in activating caspases and proinflammatory genes (5). On the other hand, ischemia-induced activation of two antiapoptotic enzymes, Bcl2 and BclXL, was enhanced (4), suggesting that activating MC4R up-regulates this putative endogenous neuroprotective pathway (13).
At a functional level, NDP-MSH treatment blocked the ischemia-induced impairment of spatial learning and memory for at least 12 d, perhaps reflecting in part the MC4R-mediated reduction of hippocampal cell death. Remarkably, the highest dose of NDP-MSH actually enhanced learning vs. that in nonischemic controls. The latter effect could involve established neurotrophic actions of melanocortins, including promotion of neurite sprouting and functional recovery from nerve injury (14). Earlier, a hypoxic-ischemic brain injury in rats was found to increase MC4R mRNA levels in the contralateral (uninjured) striatum (15), a region involved in movement planning and executive function, which is impaired after transient global ischemia (16). Such MC4R up-regulation might reflect a role of endogenous melanocortins in promoting adaptive transfer of functions to the undamaged hemisphere (15), consistent with the increased neural plasticity and functional reliance on the contralateral hemisphere that occur during stroke recovery (17). Hence, the present MC4R-mediated improvement of behavioral outcomes (4) may involve neuroprotective actions, regenerative trophic effects, or promotion of adaptive plasticity, in addition to suppression of damage pathways (Fig. 1
).
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Real or Illusory Promise in this Line of Defense? |
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TopIntroductionPathways of Destruction,...Melanocortins Protect the...Real or Illusory Promise...References |
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-MSH suppressed the elevated TNF- and IL1-ß expression seen in the perfusion territory of the occluded middle cerebral artery, and reduced cortical/striatal TNF- levels after global forebrain ischemia (19). Similar actions may contribute to reported protective effects of melanocortins in systemic and peripheral organ ischemia-reperfusion injury models. For example, -MSH treatment reduced organ damage resulting from renal or splanchnic ischemia-reperfusion in rodents, by actions including reduced expression of ICAM-1, TNF-, iNOS, and other leukocytic inflammatory markers, even when treatment was delayed for 6 h in the case of renal ischemia (reviewed in Ref.20). Melanocortins also reportedly reduced injury and death in myocardial ischemia-reperfusion, while preventing the large surge in blood-borne free radicals (presumably ROS) occurring within 2 min of coronary reperfusion (20, 21), perhaps reflecting protection against mitochondrial and cell membrane failure.
The effectiveness of delayed NDP-MSH treatment in cerebral ischemia (4) is significant because researchers seek to extend the therapeutic window of stroke therapies to many hours after symptom onset. In this connection, blocking JNK (22) or p38 (23) activity in focal ischemia models with intracerebrally applied inhibitors dramatically reduced the resulting infarct volumes, motor impairments (22), or intracerebral TNF-, IL-1ß, iNOS, and COX-2 expression (23), even when treatments were delayed 6–12 h, reflecting their roles in activating the delayed waves of inflammatory processes and cell death. NDP-MSH suppressed global ischemia-induced JNK and p38 activation after similar treatment delays (4), suggesting that this pathway could mediate the neuroprotective effects of delayed MC4R activation. Also, whereas the blood-brain barrier can present a major obstacle to prospective stroke pharmacotherapies, the efficacy of ip NDP-MSH treatment indicates that it had sufficient access systemically to the relevant MC4R-expressing cells, either within the brain parenchyma or in systemically exposed elements of the neurovascular unit. It is unknown whether nonneuronal elements of the neurovascular unit express MC4R, but melanocortins reportedly suppress NF-B activation and expression of TNF- and iNOS in activated microglia and peripheral macrophages, and also inhibited their induction within rat hypothalamus in vivo by actions attributed to MC4R (20, 24). Antipyretic actions of melanocortins could also potentially help protect against stroke-induced neural damage. Patients often present with or develop elevated body temperature after stroke, and even mild increments in body temperature exacerbate outcomes in animal models and clinical studies alike (5, 25). Both -MSH and ACTH suppress fever, and in rats the antipyretic effect of -MSH is mediated by MC4R, acting within the CNS (26).
Other factors also augur favorably concerning the feasibility of MC4R-targeted neuroprotective strategies. A nonselective MC3R/MC4R agonist peptide (PT-141) showed apparent safety and efficacy in clinical trials for treatment of erectile dysfunction (27). Like -MSH and ACTH in animal studies (28), PT-141 had no significant effects on cardiac function and blood pressure (27)—a critical concern for prospective stroke treatments. Melanocortins also lack immunogenicity, which caused inflammation, adverse events and premature termination of clinical trials of a neutrophil-targeted monoclonal antibody in stroke patients (5). Also, treatment with a high dose of ACTH-(1–24), which is a nonselective agonist at other MCR subtypes in addition to its classic adrenocortical receptor, MC2R, reportedly had dramatic, life-saving effects in patients with aortic dissection, a form of hemorrhagic shock, associated with reduced plasma TNF- levels and improved cardiovascular function (29). The mechanisms involved are not clear, but the authors found similar, adrenal-independent effects of ACTH in rat models of hemorrhagic shock, which they attributed to a descending vagal pathway, activated within the CNS by the MC4R (20, 30).
Eludidating the MC4R-expressing cells and downstream mechanisms that mediate the neuroprotective actions of melanocortins may prove challenging given their broad range of potential cellular and molecular targets within the neurovascular unit, perhaps involving overlapping or redundant pathways. An interesting question that arises is whether NDP-MSH acts directly on neuronal MC4R to suppress apoptosis, e.g. by up-regulating antiapoptotic enzymes or suppressing TNF- or COX-2 expression, which are increased in injured neurons (5). The physiological role of the constitutively expressed MC4R in hippocampal and cortical neurons has been a conundrum, because these cells do not seem to receive significant innervation by melanocortin-producing neurons (31). Or, could postischemic MC4R activation engage networks of intracerebral, neuroprotective neurons—analogous to a recently described descending vagal cholinergic antiinflammatory pathway (32), thought to suppress peripheral inflammatory responses, TNF- expression, and ischemia-reperfusion injury by activating cholinergic receptors on tissue macrophages?
Whether MC4R-directed neuroprotective strategies will show further promise toward new stroke therapies is an open question. Given the wealth of positive indicators and the seeming absence of contraindications, this seems an inviting problem for interdisciplinary attack, and an opportunity to assess the translational potential of the widely reported and multifacted antiinflammatory actions of melanocortins (20), by developing sufficient preclinical evidence to determine whether clinical trials of such therapies are warranted in this desperate patient population.
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Footnotes |
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-MSH; NF-B, nuclear factor-B; p38, MAPK p38; ROS, reactive oxidative species; RNS, reactive nitrosative species. Received December 13, 2005.
Accepted for publication December 13, 2005.
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References |
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TopIntroductionPathways of Destruction,...Melanocortins Protect the...Real or Illusory Promise...References |
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-melanocyte stimulating hormone on canine brain stem ischemia. Neurosurgery 40:132–139[CrossRef][Medline]-MSH suppresses intracerebral TNF- and IL-1ß gene expression following transient cerebral ischemia in mice. Neurosci Lett 334:186–190[CrossRef][Medline]-Melanocyte-stimulating hormone through melanocortin-4 receptor inhibits nitric oxide synthase and cyclooxygenase expression in the hypothalamus of male rats. Neuroendocrinology 79:278–286[CrossRef][Medline]This article has been cited by other articles:
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  T. Brzoska, T. A. Luger, C. Maaser, C. Abels, and M. Bohm {alpha}-Melanocyte-Stimulating Hormone and Related Tripeptides: Biochemistry, Antiinflammatory and Protective Effects in Vitro and in Vivo, and Future Perspectives for the Treatment of Immune-Mediated Inflammatory Diseases Endocr. Rev., August 1, 2008; 29(5): 581 - 602. [Abstract] [Full Text] [PDF]
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 C. Caruso, D. Durand, H. B. Schioth, R. Rey, A. Seilicovich, and M. Lasaga Activation of Melanocortin 4 Receptors Reduces the Inflammatory Response and Prevents Apoptosis Induced by Lipopolysaccharide and Interferon-{gamma} in Astrocytes Endocrinology, October 1, 2007; 148(10): 4918 - 4926. [Abstract] [Full Text] [PDF]
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