Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia.

Abstract

Ischemic stroke is one of the main causes of death and disability. We investigated whether melanocortin peptides, which have protective effects in severe hypoxic conditions, also produce neuroprotection in a gerbil model of ischemic stroke. A 10-min period of global cerebral ischemia, induced by occluding both common carotid arteries, caused impairment in spatial learning and memory that was associated with activation of inflammatory and apoptotic pathways, including severe DNA damage and delayed neuronal death, in the hippocampus. Treatment with nanomolar doses of the melanocortin analog [Nle4, D-Phe7] alpha-MSH [which activates the melanocortin receptor subtypes (MC) mainly expressed in central nervous system, namely MC3 and MC4] modulated the inflammatory and apoptotic cascades and reduced hippocampus injuries even when delayed up to 9 h after ischemia, with consequent dose-dependent improvement in subsequent functional recovery. The selective MC3 receptor agonist gamma2-MSH had no protective effects. Pharmacological blockade of MC4 receptors prevented the neuroprotective effects of [Nle4, D-Phe7] alpha-MSH and worsened some ischemia outcomes. Together, our findings suggest that MC4 receptor-stimulating melanocortins might provide potential to develop a class of drugs with a broad treatment window for a novel approach to neuroprotection in ischemic stroke.

• Authors: Daniela Giuliani, Chiara Mioni, Domenica Altavilla, Sheila Leone, Carla Bazzani, Letteria Minutoli, Alessandra Bitto, Maria-Michela Cainazzo, Herbert Marini, Davide Zaffe, Annibale R Botticelli, Roberto Pizzala, Monica Savio, Daniela Necchi, Helgi B Schiöth, Alfio Bertolini, Francesco Squadrito, Salvatore Guarini
• Journal: Endocrinology (Endocrinology) Vol. 147 Issue 3 Pg. 1126-35 (Mar 2006) ISSN: 0013-7227 [Print] United States
• PMID: 16254026 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• MC4R protein, human
• Neuroprotective Agents
• Receptor, Melanocortin, Type 4
• bcl-2-Associated X Protein
• bcl-X Protein
• alpha-MSH
• CASP3 protein, human
• Caspase 3
• Caspases

Topics

• Animals
• Apoptosis
• Blotting, Western
• Brain (metabolism, pathology)
• Brain Ischemia (pathology, therapy)
• Caspase 3
• Caspases (metabolism)
• Central Nervous System
• Cytokines (metabolism)
• Cytoplasm (metabolism)
• DNA Damage
• Disease Models, Animal
• Enzyme Activation
• Gerbillinae
• Hippocampus (metabolism)
• Hypoxia (therapy)
• Inflammation
• Ischemia (metabolism)
• Learning
• MAP Kinase Signaling System
• Male
• Maze Learning
• Memory
• Models, Statistical
• Neurons (metabolism)
• Neuroprotective Agents (pharmacology)
• Receptor, Melanocortin, Type 4 (metabolism, therapeutic use)
• Stroke (therapy)
• Time Factors
• Treatment Outcome
• alpha-MSH (metabolism)
• bcl-2-Associated X Protein (metabolism)
• bcl-X Protein (metabolism)