Giuliani Daniela, Bitto Alessandra, Galantucci Maria, Zaffe Davide, Ottani Alessandra, Irrera Natasha, Neri Laura, Cavallini Gian Maria, Altavilla Domenica, Botticelli Annibale R, Squadrito Francesco, Guarini Salvatore
Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
Neurobiol Aging. 2014 Mar;35(3):537-47. doi: 10.1016/j.neurobiolaging.2013.08.030. Epub 2013 Oct 1.
Besides specific triggering causes, Alzheimer's disease (AD) involves pathophysiological pathways that are common to acute and chronic neurodegenerative disorders. Melanocortins induce neuroprotection in experimental acute neurodegenerative conditions, and low melanocortin levels have been found in occasional studies performed in AD-type dementia patients. Here we investigated the possible neuroprotective role of melanocortins in a chronic neurodegenerative disorder, AD, by using 12-week-old (at the start of the study) triple-transgenic (3xTg-AD) mice harboring human transgenes APPSwe, PS1M146V, and tauP301L. Treatment of 3xTg-AD mice, once daily until the end of the study (30 weeks of age), with the melanocortin analog [Nle(4),D-Phe(7)]-α-melanocyte-stimulating hormone (NDP-α-MSH) reduced cerebral cortex/hippocampus phosphorylation/level of all AD-related biomarkers investigated (mediators of amyloid/tau cascade, oxidative/nitrosative stress, inflammation, apoptosis), decreased neuronal loss, induced over-expression of the synaptic activity-dependent gene Zif268, and improved cognitive functions, relative to saline-treated 3xTg-AD mice. Pharmacological blockade of melanocortin MC4 receptors prevented all neuroprotective effects of NDP-α-MSH. Our study identifies, for the first time, a class of drugs, MC4 receptor-stimulating melanocortins, that are able to counteract the progression of experimental AD by targeting pathophysiological mechanisms up- and down-stream of β-amyloid and tau. These data could have important clinical implications.
除了特定的触发因素外，阿尔茨海默病（AD）还涉及急性和慢性神经退行性疾病共有的病理生理途径。黑素皮质素在实验性急性神经退行性疾病中具有神经保护作用，并且在对AD型痴呆患者进行的偶尔研究中发现黑素皮质素水平较低。在这里，我们通过使用携带人类转基因APPSwe、PS1M146V和tauP301L的12周龄（研究开始时）三转基因（3xTg-AD）小鼠，研究了黑素皮质素在慢性神经退行性疾病AD中可能的神经保护作用。用黑素皮质素类似物[Nle(4),D-Phe(7)]-α-黑素细胞刺激素（NDP-α-MSH）对3xTg-AD小鼠进行每日一次的治疗，直至研究结束（30周龄），与用生理盐水处理的3xTg-AD小鼠相比，降低了所研究的所有AD相关生物标志物（淀粉样蛋白/tau级联反应的介质、氧化/亚硝化应激、炎症、细胞凋亡）的大脑皮质/海马磷酸化/水平，减少了神经元损失，诱导了突触活性依赖性基因Zif268的过表达，并改善了认知功能。黑素皮质素MC4受体的药理学阻断阻止了NDP-α-MSH的所有神经保护作用。我们的研究首次确定了一类药物，即刺激MC4受体的黑素皮质素，它们能够通过靶向β-淀粉样蛋白和tau上下游的病理生理机制来对抗实验性AD的进展。这些数据可能具有重要的临床意义。
