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2.
Crit Care Med ; 39(5): 1089-96, 2011 May.
Article in English | MEDLINE | ID: mdl-21263321

ABSTRACT

OBJECTIVE: Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure. Melanocortin peptides have been successfully used in experimental models of organ failure and shock, and their protective effect occurs through the activation of a vagus nerve-mediated cholinergic anti-inflammatory pathway by acting at brain melanocortin 4 receptors. In the light of these observations, we studied the effects of the selective melanocortin 4 receptor agonist RO27-3225 in an experimental model of cerulein-induced pancreatitis. DESIGN: Randomized experiment. SETTING: Research laboratory at a university hospital. SUBJECT: Experimental pancreatitis in rats. INTERVENTIONS: Acute pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal injections of cerulein (80 µg/kg, four injections at hourly intervals). Before pancreatitis induction, groups of animals were subjected to bilateral cervical vagotomy, pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective melanocortin 4 receptor antagonist HS024, or not pretreated. Thirty minutes after the first cerulein injection, rats were intraperitoneally treated with a nanomolar dose of RO27-3225 or vehicle. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 mins after treatment with RO27-3225 or vehicle, and for a 30-min period. MEASUREMENTS AND MAIN RESULTS: Serum lipase and amylase activity, tumor necrosis factor-α and interleukin-6 expression, pancreatic myeloperoxidase activity, and histologic damage were evaluated; neural efferent activity of vagal fibers was also assessed. RO27-3225 reduced cerulein-induced serum lipase and amylase activity, blunted the expression of tumor necrosis factor-α and interleukin-6, abated the increase in pancreatic myeloperoxidase activity, and protected against histologic damage. Furthermore, RO27-3225 markedly increased neural efferent activity along the vagus nerve. Vagotomy, chlorisondamine, and HS024 abated these protective effects of RO27-3225. CONCLUSIONS: Our data show that melanocortin 4 receptor agonists reduce pancreatitis severity through the activation of the cholinergic anti-inflammatory pathway. These findings could be of particular interest in the clinical setting.


Subject(s)
Cholinergic Agents/metabolism , Pancreatitis/drug therapy , Pancreatitis/pathology , Peptides/pharmacology , Receptor, Melanocortin, Type 4/agonists , Signal Transduction/drug effects , Acute Disease , Analysis of Variance , Animals , Blotting, Western , Ceruletide/pharmacology , Disease Models, Animal , Immunohistochemistry , Inflammation Mediators/metabolism , Interleukin-6/metabolism , Male , Pancreatitis/chemically induced , Peroxidase/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Receptor, Melanocortin, Type 4/therapeutic use , Receptors, Nicotinic/metabolism , Sensitivity and Specificity , Severity of Illness Index , Tumor Necrosis Factor-alpha/metabolism , Vagus Nerve/drug effects
3.
Endocrinology ; 147(3): 1126-35, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16254026

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.


Subject(s)
Brain Ischemia/pathology , Brain Ischemia/therapy , Neuroprotective Agents/pharmacology , Receptor, Melanocortin, Type 4/therapeutic use , Animals , Apoptosis , Blotting, Western , Brain/metabolism , Brain/pathology , 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 , Receptor, Melanocortin, Type 4/metabolism , Stroke/therapy , Time Factors , Treatment Outcome , alpha-MSH/metabolism , bcl-2-Associated X Protein/metabolism , bcl-X Protein/metabolism
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