Functional recovery after delayed treatment of ischemic stroke with melanocortins is associated with overexpression of the activity-dependent gene Zif268.
Giuliani. Daniela D; Ottani. Alessandra A; Minutoli. Letteria L; Stefano. Vincenzo Di VD; Galantucci. Maria M; Bitto. Alessandra A; Zaffe. Davide D; Altavilla. Domenica D; Botticelli. Annibale R AR; Squadrito. Francesco F; Guarini. Salvatore S
Key Findings
- A nanomolar dose of NDP‑α‑MSH administered every 12 hours for 11 days, starting 3–9 hours after global cerebral ischemia, markedly reduced hippocampal neuron loss.
- Treated gerbils showed lasting improvement in Morris water‑maze learning and memory up to 50 days post‑stroke.
- The protective effect required MC4‑receptor activation and was associated with over‑expression of the activity‑dependent gene Zif268.
Practical Outcomes
- The study suggests melanotan‑I could act as a neuroprotective agent if given soon after a stroke, but the protocol (nanomolar dosing, repeated injections for days, MC4‑receptor specificity) is far from ready for self‑administration. For biohackers, the main takeaway is that melanocortin signaling has brain‑repair potential, yet safe, effective dosing and delivery methods need much more research before any real‑world use.
Summary
In a gerbil stroke model, giving the melanocortin peptide NDP‑α‑MSH (the same molecule sold as melanotan‑I) a few hours after a brain attack reduced damage and helped the animals learn and remember better for weeks. The benefit depended on activating the MC4 receptor and was linked to higher levels of a brain‑repair gene called Zif268.
Abstract
Melanocortin peptides afford strong neuroprotection and improve functional recovery in experimental ischemic stroke; they also have established neurotrophic actions. The expression of the immediate early gene Zif268 is dependent on synaptic activity and is involved in injury repair and memory formation. Here, we investigated the role of Zif268 in learning and memory recovery after delayed treatment of ischemic stroke with the melanocortin analog [Nle(4), D-Phe(7)]alpha-MSH (NDP-alpha-MSH). A 10-min period of global cerebral ischemia was induced by occluding both common carotid arteries in gerbils. Treatment with a nanomolar dose of NDP-alpha-MSH (every 12h for 11 days) was performed starting 3h or 9h after stroke induction; where indicated, gerbils were pretreated with the melanocortin MC(4) receptor antagonist HS024. Animals were subjected to the Morris water-maze test (four sessions from 4 to 50 days after the ischemic episode). Fifty days after stroke, histological damage and Zif268 expression were investigated in the hippocampus. Treatment with NDP-alpha-MSH significantly reduced hippocampal damage, including neuronal death, and improved learning and memory recovery. This protective effect was long-lasting (50 days, at least) and associated with Zif268 overexpression, with both schedules of NDP-alpha-MSH treatment. Pharmacological blockade of MC(4) receptors prevented these effects. Our data indicate that MC(4) receptor-mediated actions of melanocortins could trigger repair mechanisms able to improve neuronal functionality and synaptic plasticity, and to promote long-lasting functional recovery from ischemic stroke with Zif268 gene involvement.
Study Information
pubmed
2009
2009-04-05T00:00:00.000Z
10.1016/j.bbi.2009.03.009
38
39