NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors.
Giuliani. Daniela D; Neri. Laura L; Canalini. Fabrizio F; Calevro. Anita A; Ottani. Alessandra A; Vandini. Eleonora E; Sena. Paola P; Zaffe. Davide D; Guarini. Salvatore S
Key Findings
- NDP‑α‑MSH treatment improved cognitive performance in AD mice
- The peptide increased neurogenesis in the hippocampus, with more new mature neurons
- Blocking MC4 receptors stopped the cognitive and neurogenic benefits
- No toxicity was observed in the treated mice
Practical Outcomes
- The results are promising but only in mice; there’s no human safety or dosing data yet. For now, it’s a signal that MC4‑activating compounds might one day help brain health, but self‑experimentation with melanotan‑I for Alzheimer’s or cognition is not advised until clinical trials confirm safety and efficacy.
Summary
A study in Alzheimer‑model mice found that daily low‑dose injections of the peptide NDP‑α‑MSH (melanotan‑I) improved memory and boosted the creation of new brain cells, without obvious side effects. The benefits disappeared when a drug that blocks the MC4 receptor was given, showing the effect depends on that receptor.
Abstract
Melanocortins exert neuroprotection in a variety of experimental neurodegenerative disorders, including Alzheimer's disease (AD). Further, in previous research we showed that these endogenous peptides stimulate neurogenesis in an acute neurodegenerative disorder such as ischemic stroke. In the present research, we investigated the potential neurogenic effect of melanocortins in AD using APPSwe transgenic mice (Tg2576). To this purpose, 24week-old animals were prepared for 5-bromo-2'-deoxyuridine (BrdU) labeling of proliferating cells on days 1-11 of the study. Treatment of Tg2576 mice with nanomolar doses of the melanocortin analog [Nle(4),D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH), administered once daily from day 1 to 50, improved brain histology and cognitive functions relative to saline-treated Tg2576 animals. No signs of toxicity were observed. Immunohistochemical examination of the hippocampus at the end of the study (day 50) showed that NDP-α-MSH-treated Tg2576 mice had a greater number of BrdU immunoreactive cells colocalized with NeuN (an indicator of mature neurons) and Zif268 (an indicator of functionally integrated neurons) in the dentate gyrus, relative to saline-treated Tg2576 animals; no newly formed astrocytes were found. Animal pretreatment with the selective melanocortin MC4 receptor antagonist HS024 before each NDP-α-MSH administration prevented all the beneficial effects of the peptide. The present data indicate that MC4 receptor stimulation by a melanocortin prevents cognitive decline in experimental AD, this effect being associated not only with neuroprotection but also with an intense neurogenesis. MC4 receptor agonists could be innovative and safe candidates to counteract AD progression in humans.
Study Information
pubmed
2015
2015-05-21T00:00:00.000Z
10.1016/j.mcn.2015.05.004
37
69