Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer%26apos;s disease

作者：Giuliani Daniela^*; Galantucci Maria; Neri Laura; C****ini Fabrizio; Calevro Anita; Bitto Alessandra; Ottani Alessandra; Vandini Eleonora; Sena Paola; Sandrini Maurizio; Squadrito Francesco; Zaffe Davide; Guarini Salvatore

来源：European Journal of Pharmacology, 2014, 740: 144-150.

DOI：10.1016/j.ejphar.2014.06.063

• Alzheimer%26apos
• s disease
• Tg2576 mice
• Melanocortins
• Learning and memory
• Zif268
• Neuroprotection

We previously reported that melanocortins induce neuroprotection in experimental acute and chronic neurodegenerative conditions, including Alzheimer%26apos;s disease (AD) of mild severity. Here we investigated whether melanocortins afford neuroprotection and counteract cognitive decline in AD with a medium level of severity by using 24 week-old (at the start of the study) APP(Swe) transgenic mice (Tg2576). Saline-treated (clays 1-50) control Tg2576 mice showed an impairment in spatial learning and memory, associated (at day 50, end of the study) with hippocampus at low levels of the synaptic activity-dependent gene Zif268, relevant brain changes such as cerebral cortex/hippocampus increased level of beta-amyloid (A beta)) deposit, and neuronal loss, in comparison with wild-type animals. Treatment of Tg2576 mice (once daily at days 1-50) with a nanomolar close of the melanocortin analog [Nle(4),D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) reduced cerebral cortex/hippocampus level of A beta) deposit, decreased neuronal loss, increased hippocampus Zif268 expression and improved cognitive functions, relative to saline treated Tg2576 mice. Pharmacological blockade of melanocortin MC4 receptors with the MC4 receptor antagonist HS024 prevented all favorable effects of NDP-a-MSH. Our data indicate that MC4 receptor stimulating melanocortins are able to counteract cognitive decline in experimental AD of medium severity through induction of neuroprotection and improvement of synaptic transmission. After further studies, these agents could gain a role as disease modifying therapeutics for AD.

• 出版日期2014-10-5