ABSTRACT
Title
Direct evidence that melanocortin MC4 receptor stimulation induces neuroprotection against ischemic stroke
Authors
A. Ottani1, A. Bitto2, L. Spaccapelo1, M. Galantucci1, L. Minutoli2, D. Altavilla2, E. Novellino3, P. Grieco3, D. Zaffe4, F. Squadrito2, D. Giuliani1and S. Guarini1.
1 Dept. of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Italy
2 Dept. of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
3 Dept. of Pharmaceutical Chemistry and Toxicology, University of Napoli “Federico II”, Italy
4 Dept. of Biomedical Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Italy
1 Dept. of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Italy
2 Dept. of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy
3 Dept. of Pharmaceutical Chemistry and Toxicology, University of Napoli “Federico II”, Italy
4 Dept. of Biomedical Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Italy
Abstract
In experimental ischemic stroke and traumatic brain injury, melanocortins have neuroprotective effects likely mediated by MC4 receptors (Giuliani et al., 2006a,b,2007,2009; Ottani et al., 2009; Bitto et al., 2011). To gain direct insight into the role of melanocortin MC4 receptors in stroke conditions, we investigated the effects of a highly selective MC4 receptor agonist. Gerbils were subjected to transient global cerebral ischemia by occluding both common carotid arteries for 10 min. In saline-treated stroke animals, an impairment in learning and memory occurred that, at day 11 after stroke, was associated with hippocampus up-regulation of tumor necrosis factor-α (TNF-α), BAX, activated extracellular signal-regulated kinases (ERK1/2), c-jun N-terminal kinases (JNK1/2) and caspase-3, down-regulation of Bcl-2, and neuronal loss. Treatment for 11 days with the selective melanocortin MC4 receptor agonist RO27-3225, as well as with the non-selective [Nle4,D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) as a reference melanocortin, counteracted the inflammatory and apoptotic responses, as indicated by the changes in TNF-α, BAX, ERK1/2, JNK1/2, caspase-3 and Bcl-2 protein expression, reduced neuronal loss and dose-dependently improved learning and memory. These positive effects were associated with overexpression of Zif268, an immediate early gene involved in injury repair, synaptic plasticity and memory formation. Pharmacological blockade of MC4 receptors with the selective MC4 receptor antagonist HS024 prevented all effects of RO27-3225 and NDP-α-MSH. These data give direct evidence that stimulation of MC4receptors affords neuroprotection and promotes functional recovery from stroke, by counteracting the main ischemia-related mechanisms of damage, and likely by triggering brain repair pathways. After sufficient preclinical investigation, these findings could have major clinical implications.
Bitto et al. (2011). Submitted.
Giuliani et al. (2006a). Eur J Pharmacol. 538: 48-56.
Giuliani et al. (2006b). Endocrinology. 147: 1126-1135.
Giuliani et al. (2007). Eur J Pharmacol. 570: 57-65.
Giuliani et al. (2009). Brain Behav Immun.23: 844-850.
Ottani et al. (2009). J Cereb Blood Flow Metab. 29: 512-523.
Bitto et al. (2011). Submitted.
Giuliani et al. (2006a). Eur J Pharmacol. 538: 48-56.
Giuliani et al. (2006b). Endocrinology. 147: 1126-1135.
Giuliani et al. (2007). Eur J Pharmacol. 570: 57-65.
Giuliani et al. (2009). Brain Behav Immun.23: 844-850.
Ottani et al. (2009). J Cereb Blood Flow Metab. 29: 512-523.