Title

 

Authors

D. Giuliani¹, A. Ottani¹, M. Galantucci¹, L. Spaccapelo¹, D. Zaffe², S. Guarini¹

Dept. of Biomedical Sciences, Sections of ¹Pharmacology and ²Human Morphology, University of Modena and Reggio Emilia, Italy 

 

Abstract

Brain damage consequent to ischemic stroke and traumatic brain injury (TBI) is caused by several mechanisms, including excitotoxicity, inflammatory response, defective autophagy and apoptosis. The novel therapeutic approaches failed and today there is no clinically proven therapy for these conditions. Despite the different triggering causes, a number of pathophysiological pathways − leading to damage and neuronal death – are common to all acute and chronic neurodegenerative diseases (1,2). Therapeutically promising, neuroprotective properties of melanocortins − endogenous peptides of the ACTH/MSH group − arise from studies carried out in several models of brain injury. Indeed, short-term treatment with nanomolar amounts of these neuropeptides afford a strong neuroprotection against damage consequent to global or focal cerebral ischemia in dogs, mice, gerbils and rats, and to TBI in rats (3-6). Interestingly, this protective effect occurs also when treatment starts several hours after ischemia or TBI. In these experimental models of brain injury, the melanocortin-induced functional recovery (e.g., learning, memory, sensory-motor orientation and coordinated limb use) is accompanied by a reduction of morphological damage in the brain areas investigated, with a higher number of viable neurons, as compared with that of saline-treated stroke or TBI animals. Experimental evidence indicates that such neuroprotective effects occur through a counteraction of the main ischemia-related mechanisms of damage, namely the excitotoxic, inflammatory and apoptotic responses. Interestingly, melanocortins also increase serum levels of the anti-inflammatory cytokine interleukin-10 and brain expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Overall, these mechanisms lead to decrease in DNA fragmentation. Of note, functional recovery induced by melanocortins after ischemic stroke and TBI is long-lasting. Consistently, it has recently been found that treatment of stroke gerbils with the synthetic melanocortin agonist NDP-α-MSH gives rise to a marked increase in the number of hippocampus cells labeled with 5-bromo-2’-deoxyuridine (BrdU), a thymidine analog intraperitoneally injected to animals to label proliferating cells. At confocal microscopy examination performed 50 days after stroke, many double-labeled BrdU-NeuN cells were found within the dentate gyrus (DG) of NDP-α-MSH-treated stroke animals, and no double-labeled BrdU-GFAP cells (newly formed astrocytes) were detected, this indicating that melanocortin treatment shifts toward the neuronal phenotype. Furthermore, in NDP-α-MSH-treated stroke gerbils almost all BrdU-NeuN immunoreactive cells colocalized with the early functional gene Zif268, used as indicator of functionally integrated neurons. Notably, the number of triple-labeled BrdU-NeuN-Zif268 cells counted in the DG was about 15-fold higher than that of saline-treated stroke animals (7). Melanocortin MC₄ receptors, the predominant melanocortin receptor subtypes in the CNS (8), seem to be involved in protective effects of melanocortins against stroke and TBI.
Overall, induction of neuroprotection in a broad time window, and generation of new cells which develop properties of mature and functional neurons in the brain injured areas, depict an interesting pharmacological profile of melanocortins.These neuropeptides and synthetic analogs could provide potential to develop a new class of drugs for an innovative approach to treatment of ischemic stroke and TBI, and perhaps other neurodegenerative diseases, in humans.

1. Haass (2010).Nat Med. 16:1201-1204.
2. Lo (2010). Nat Med. 16:1205-1209.
3. Giuliani et al. (2006). Endocrinology. 147:1126-1135.
4. Giuliani et al. (2007). Eur J Pharmacol. 570:57-65.
5. Giuliani et al. (2009). Brain Behav Immun. 23:844-850.
6. Bitto et al. (2011). Submitted.
7. Giuliani et al. (2011). Submitted.
8. Catania (2008). Trends Neurosci.31:353-360.