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Treatment of cerebral ischemia with melanocortins acting at MC4 receptors induces marked neurogenesis and long-lasting functional recovery

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Abstract

Melanocortins produce neuroprotection against ischemic stroke with subsequent long-lasting functional recovery, through melanocortin MC4 receptor activation. Here we investigated whether the long-lasting beneficial effect of melanocortins in stroke conditions is associated with a stimulation of neurogenesis. Gerbils were subjected to transient global cerebral ischemia by occluding both common carotid arteries for 10 min; then, they were prepared for 5-bromo-2′-deoxyuridine (BrdU) labeling of proliferating cells. Delayed treatment (up to 9 h after the ischemic injury) for 11 days with the melanocortin analog [Nle4,d-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) improved learning and memory throughout the 50-day observation period. Immunohistochemical examination of the hippocampus on day 50 showed, in the dentate gyrus, an elevated number of BrdU immunoreactive cells colocalized with NeuN (used as indicator of mature neurons) and Zif268 (used as indicator of functionally integrated neurons). Retrospective analysis during the early stage of neural stem/progenitor cell development (days 3 and 4 after stroke) showed, in NDP-α-MSH-treated gerbils, a high degree of daily cell proliferation and revealed that NDP-α-MSH favorably affects Wnt-3A signaling pathways and doublecortin expression. Pharmacologic blockade of MC4 receptors prevented all effects of NDP-α-MSH. These data indicate that treatment of cerebral ischemia with MC4 receptor agonists induces, with a broad window of therapeutic opportunity, long-lasting functional recovery associated with a large number of mature and likely functional newborn neurons in brain injured areas. Our findings reveal previously undescribed effects of melanocortins which might have major clinical implications.

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References

  1. Adams HP, Del Zoppo G, Alberts MJ et al (2007) Guidelines for the early management of adults with ischemic stroke. Stroke 38:1655–1711

    Article  PubMed  Google Scholar 

  2. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

    Article  PubMed  CAS  Google Scholar 

  3. Arvidsson A, Kokaia Z, Lindvall O (2001) N-methyl-d-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci 14:10–18

    Article  PubMed  CAS  Google Scholar 

  4. Baldwin K, Orr S, Briand M, Piazza C, Veydt A, McCoy S (2010) Acute ischemic stroke update. Pharmacotherapy 30:493–514

    Article  PubMed  Google Scholar 

  5. Banks WA, Kastin AJ (1995) Permeability of the blood–brain barrier to melanocortins. Peptides 16:1157–1161

    Article  PubMed  CAS  Google Scholar 

  6. Becker M, Lavie V, Solomon B (2007) Stimulation of endogenous neurogenesis by anti-EFRH immunization in a transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 104:1691–1696

    Article  PubMed  CAS  Google Scholar 

  7. Beckmann AM, Wilce PA (1997) Egr transcription factors in the nervous system. Neurochem Int 31:477–510

    Article  PubMed  CAS  Google Scholar 

  8. Bitto A, Polito F, Altavilla D et al (2011) Melanocortins protect against multiple organ dysfunction syndrome in mice. Br J Pharmacol 162:917–928

    Article  PubMed  CAS  Google Scholar 

  9. Burns TC, Verfaillie CM, Low WC (2009) Stem cells for ischemic brain injury: a critical review. J Comp Neurol 515:125–144

    Article  PubMed  Google Scholar 

  10. Catania A (2008) Neuroprotective actions of melanocortins: a therapeutic opportunity. Trends Neurosci 31:353–360

    Article  PubMed  CAS  Google Scholar 

  11. Chen G, Frokiaer J, Pedersen M et al (2008) Reduction of ischemic stroke in rat brain by alpha melanocyte stimulating hormone. Neuropeptides 42:331–338

    Article  PubMed  CAS  Google Scholar 

  12. Corander MP, Fenech M, Coll AP (2009) Science of self-preservation: how melanocortin action in the brain modulates body weight, blood pressure, and ischemic damage. Circulation 120:2260–2268

    Article  PubMed  Google Scholar 

  13. Duan X, Kang E, Liu CY, Ming GL, Song H (2008) Development of neural stem cell in the adult brain. Curr Opin Neurobiol 18:108–115

    Article  PubMed  CAS  Google Scholar 

  14. Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438

    Article  PubMed  CAS  Google Scholar 

  15. Giuliani D, Leone S, Mioni C et al (2006) Broad therapeutic treatment window of the [Nle4, d-Phe7]α-melanocyte-stimulating hormone for long-lasting protection against ischemic stroke, in Mongolian gerbils. Eur J Pharmacol 538:48–56

    Article  PubMed  CAS  Google Scholar 

  16. Giuliani D, Mioni C, Altavilla D et al (2006) Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology 147:1126–1135

    Article  PubMed  CAS  Google Scholar 

  17. Giuliani D, Ottani A, Altavilla D, Bazzani C, Squadrito F, Guarini S (2010) Melanocortins and the cholinergic anti-inflammatory pathway. Adv Exp Med Biol 681:71–87

    Article  PubMed  CAS  Google Scholar 

  18. Giuliani D, Ottani A, Minutoli L et al (2009) Functional recovery after delayed treatment of ischemic stroke with melanocortins is associated with overexpression of the activity-dependent gene Zif268. Brain Behav Immun 23:844–850

    Article  PubMed  CAS  Google Scholar 

  19. Giuliani D, Ottani A, Mioni C et al (2007) Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins. Eur J Pharmacol 570:57–65

    Article  PubMed  CAS  Google Scholar 

  20. Gladstone DJ, Black SE, Hakim AM (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33:2123–2136

    Article  PubMed  Google Scholar 

  21. Guarini S, Bazzani C, Bertolini A (1997) Resuscitating effect of melanocortin peptides after prolonged respiratory arrest. Br J Pharmacol 121:1454–1460

    Article  PubMed  CAS  Google Scholar 

  22. Guarini S, Tagliavini S, Bazzani C (1990) Early treatment with ACTH-(1–24) in a rat model of hemorrhagic shock prolongs survival and extends the time-limit for blood reinfusion to be effective. Crit Care Med 18:862–865

    Article  PubMed  CAS  Google Scholar 

  23. Huang Q, Tatro JB (2002) α-Melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-α and interleukin-1β gene expression following transient cerebral ischemia in mice. Neurosci Lett 334:186–190

    Article  PubMed  CAS  Google Scholar 

  24. Inestrosa NC, Arenas E (2010) Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11:77–86

    Article  PubMed  CAS  Google Scholar 

  25. Kuwabara T, Hsieh J, Muotri A et al (2009) Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci 12:1097–1105

    Article  PubMed  CAS  Google Scholar 

  26. Lichtenwalner RJ, Parent JM (2006) Adult neurogenesis and the ischemic forebrain. J Cereb Blood Flow Metab 26:1–20

    Article  PubMed  CAS  Google Scholar 

  27. Liu J, Solway K, Messing RO, Sharp FR (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18:7768–7778

    PubMed  CAS  Google Scholar 

  28. Liu YP, Lang BT, Baskaya MK, Dempsey RJ, Vemuganti R (2009) The potential of neural stem cells to repair stroke-induced brain damage. Acta Neuropathol 117:469–480

    Article  PubMed  Google Scholar 

  29. Mioni C, Bazzani C, Giuliani D et al (2005) Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats. Crit Care Med 33:2621–2628

    Article  PubMed  CAS  Google Scholar 

  30. Morita Y, Takizawa S, Kamiguchi H, Uesugi T, Kawada H, Takagi S (2007) Administration of hematopoietic cytokines increases the expression of anti-inflammatory cytokine (IL-10) mRNA in the subacute phase after stroke. Neurosci Res 58:356–360

    Article  PubMed  CAS  Google Scholar 

  31. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198

    Article  PubMed  CAS  Google Scholar 

  32. Mountjoy KG (2010) Distribution and Function of Melanocortin Receptors within the Brain. Adv Exp Med Biol 681:29–48

    Article  PubMed  CAS  Google Scholar 

  33. Noera G, Lamarra M, Guarini S, Bertolini A (2001) Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1–24). Lancet 358:469–470

    Article  PubMed  CAS  Google Scholar 

  34. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW (2006) 1,026 experimental treatments in acute stroke. Ann Neurol 59:467–477

    Article  PubMed  Google Scholar 

  35. Ottani A, Giuliani D, Mioni C et al (2009) Vagus nerve mediates the protective effects of melanocortins against cerebral and systemic damage after ischemic stroke. J Cereb Blood Flow Metab 29:512–523

    Article  PubMed  CAS  Google Scholar 

  36. Rogalewski A, Schneider A, Ringelstein EB, Schäbitz WR (2006) Toward a multimodal neuroprotective treatment of stroke. Stroke 37:1129–1136

    Article  PubMed  Google Scholar 

  37. Savos AV, Gee JM, Zierath D, Becker KJ (2011) α-MSH: a potential neuroprotective and immunomodulatory agent for the treatment of stroke. J Cereb Blood Flow Metab 31:606–613

    Article  PubMed  CAS  Google Scholar 

  38. Suh H, Deng W, Gage FH (2009) Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 25:253–275

    Article  PubMed  CAS  Google Scholar 

  39. Sun Y, Jin K, Xie L et al (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:1843–1851

    PubMed  CAS  Google Scholar 

  40. Suzuki S, Gerhold LM, Bottner M et al (2007) Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. J Comp Neurol 500:1064–1075

    Article  PubMed  CAS  Google Scholar 

  41. Tashiro A, Makino H, Gage FH (2007) Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci 27:3252–3259

    Article  PubMed  CAS  Google Scholar 

  42. Tatro JB (2006) Melanocortins defend their territory: multifaceted neuroprotection in cerebral ischemia. Endocrinology 147:1122–1125

    Article  PubMed  CAS  Google Scholar 

  43. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35:1732–1737

    Article  PubMed  CAS  Google Scholar 

  44. Wikberg JE, Mutulis F (2008) Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov 7:307–323

    Article  PubMed  CAS  Google Scholar 

  45. Yepes M, Roussel BD, Ali C, Vivien D (2009) Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci 32:48–55

    Article  PubMed  CAS  Google Scholar 

  46. Zhang ZG, Chopp M (2009) Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol 8:491–500

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR; project PRIN), Roma; and University of Modena and Reggio Emilia, Italy.

Conflict of interest

The authors state no conflict of interests.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125, Modena, Italy

    Daniela Giuliani, Alessandra Ottani, Luca Spaccapelo, Maria Galantucci & Salvatore Guarini

  2. Department of Biomedical Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy

    Davide Zaffe

  3. Department of Biomedical Sciences, Section of General Pathology, University of Modena and Reggio Emilia, Modena, Italy

    Miranda Contri

  4. Department of Human Pathology, University of Pavia, Pavia, Italy

    Annibale R. Botticelli

  5. Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy

    Letteria Minutoli, Alessandra Bitto, Natasha Irrera, Domenica Altavilla & Francesco Squadrito

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  1. Daniela Giuliani
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  2. Davide Zaffe
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  3. Alessandra Ottani
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  13. Salvatore Guarini
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Correspondence to Salvatore Guarini.

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Giuliani, D., Zaffe, D., Ottani, A. et al. Treatment of cerebral ischemia with melanocortins acting at MC4 receptors induces marked neurogenesis and long-lasting functional recovery. Acta Neuropathol 122, 443–453 (2011). https://doi.org/10.1007/s00401-011-0873-4

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  • DOI: https://doi.org/10.1007/s00401-011-0873-4

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