Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
Department of Molecular and Developmental Medicine, Policlinico Le Scotte, University of Siena, Siena, Italy.
J Pineal Res. 2017 Oct;63(3). doi: 10.1111/jpi.12434. Epub 2017 Aug 7.
Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI-induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated.
越来越多的证据表明，褪黑素对各种器官的不同类型损伤具有保护作用，包括大脑。在缺氧缺血（HI）的新生动物模型中，褪黑素具有神经保护作用，并在损伤后 24 小时内保持沉默信息调节因子 1（SIRT1）的表达。本研究旨在通过研究 SIRT1 及其下游靶标的早期（1 小时）调节以及对坏死、细胞凋亡、自噬和神经胶质细胞激活的影响，进一步了解 SIRT1 在 HI 后褪黑素保护作用中的作用。我们发现，在缺血性损伤后 5 分钟给予褪黑素可显著减少损伤后 1 小时评估的坏死细胞死亡。平行的，我们发现内在细胞凋亡的早期阶段的激活减少，通过减少 BAX 向线粒体的易位和细胞色素 C 的线粒体表达的保留来检测，表明褪黑素处理的缺血动物的外线粒体膜通透性降低。这些作用与 SIRT1 的表达和活性增加、p53 的表达和乙酰化减少以及自噬激活增加同时发生。褪黑素还减少了 HI 诱导的神经胶质细胞激活。HI 和褪黑素后 SIRT1 在神经元中表达，但在表达 GFAP 的反应性神经胶质细胞中不表达。在对照条件下，在一些细胞中发现了 SIRT1 和 GFAP 之间的共定位。总之，我们的研究结果为 SIRT1 和褪黑素在神经保护中的联系提供了更多的见解。需要进一步研究褪黑素诱导的 SIRT1 活性是否有助于在神经退行性过程中分化神经元祖细胞。
