title: NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors.
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.
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: daniela.giuliani@unimore.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Neri
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Canalini
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Calevro
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vandini
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sena
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: salvatore.guarini@unimore.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D003071:Cognition; D006624:Hippocampus / Q000187:drug effects; D051379:Mice; D055495:Neurogenesis; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000378:metabolism*; D000521:alpha-MSH / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-
keywords: Alzheimer's disease; Functional integration; Learning and memory; Melanocortin MC(4) receptors; Neurogenesis; Tg2576 mice