Neuropharmacology and AnalgesiaMelanocortin MC4 receptor agonists counteract late inflammatory and apoptotic responses and improve neuronal functionality after cerebral ischemia

Indirect evidence indicates that, in cerebral ischemia, melanocortins have neuroprotective effects likely mediated by MC4 receptors. To gain direct insight into the role of melanocortin MC4 receptors in ischemic stroke, 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 well known non-selective [Nle4,D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) as a reference non-selective 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. Furthermore, melanocortin treatment 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 MC4 receptors affords neuroprotection and promotes functional recovery from stroke, by counteracting prolonged and/or recurrent inflammatory and apoptotic responses, and likely by triggering brain repair pathways.