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.

中文翻译：

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新生鼠脑缺氧缺血后褪黑素对沉默信息调节因子1的快速调节。

越来越多的证据表明褪黑激素对包括大脑在内的各种器官具有不同类型的损伤具有保护作用。在新生儿缺氧缺血（HI）模型中，褪黑激素具有神经保护作用，并在受伤后24小时保留了沉默信息调节因子1（SIRT1）的表达。这项研究旨在通过研究SIRT1的早期（1小时）调节及其下游靶点，以及对坏死，凋亡，自噬和神经胶质细胞活化的影响，来更深入地了解SIRT1在HI后褪黑激素的保护作用中的作用。 。我们发现，在缺血性损伤后5分钟给药褪黑激素可显着降低给药1小时后评估的坏死细胞死亡。同时，我们发现内在凋亡的早期阶段的激活减少，通过减少BAX易位至线粒体并保留线粒体细胞色素C的表达检测到，表明褪黑素治疗的缺血性动物体内线粒体外膜通透性降低。这些作用与增加SIRT1的表达和活性，降低p53的表达和乙酰化以及增加自噬激活有关。褪黑素也减少了HI诱导的神经胶质细胞的活化。SIRT1在HI和褪黑素后在神经元中表达，但在表达GFAP的反应性神经胶质细胞中不表达。在对照条件下的某些细胞中发现了SIRT1和GFAP之间的共定位。总之，我们的结果为神经保护中的SIRT1和褪黑激素之间的联系提供了更多的见识。