PDF(Pubmed)
Abstract：
The mutual interplay between neuroinflammation, synaptic plasticity, and autophagy has piqued researchers\' interest, particularly when it comes to linking their impact and relationship to cognitive deficits. Being able to reduce inflammation and apoptosis, melatonin has shown to have positive neuroprotective effects; that is why we thought to check the possible role of agomelatine (AGO) as a promising candidate that could have a positive impact on cognitive deficits. In the current study, AGO (40 mg/kg/day, p.o., 7 days) successfully ameliorated the cognitive and learning disabilities caused by lipopolysaccharide (LPS) in rats (250 μg/kg/day, i.p., 7 days). This positive impact was supported by improved histopathological findings and improved spatial memory as assessed using Morris water maze. AGO showed a strong ability to control BACE1 activity and to rein in the hippocampal amyloid beta (Aβ) deposition. Also, it improved neuronal survival, neuroplasticity, and neurogenesis by boosting BDNF levels and promoting its advantageous effects and by reinforcing the pTrkB expression. In addition, it upregulated the pre- and postsynaptic neuroplasticity biomarkers resembled in synapsin I, synaptophysin, and PSD-95. Furthermore, AGO showed a modulatory action on Sortilin-related receptor with A-type repeats (SorLA) pathway and adjusted autophagy. It is noteworthy that all of these actions were abolished by administering PD98059 a MEK/ERK pathway inhibitor (0.3 mg/kg/day, i.p., 7 days). In conclusion, AGO administration significantly improves memory and learning disabilities associated with LPS administration by modulating the ERK/SorLA/BDNF/TrkB signaling pathway parallel to its capacity to adjust the autophagic process.
摘要：
神经炎症之间的相互作用，突触可塑性，自噬引起了研究者的兴趣,特别是在将它们的影响和与认知缺陷的关系联系起来时。能够减少炎症和细胞凋亡，褪黑激素已显示出积极的神经保护作用;这就是为什么我们认为检查阿戈美拉汀（AGO）作为一种有希望的候选人，可能对认知缺陷产生积极影响的可能作用。在目前的研究中,AGO（40毫克/千克/天，p.o.,7天）成功改善了脂多糖（LPS）引起的大鼠认知和学习障碍（250μg/kg/天，i.p.,7天）。如使用Morris水迷宫评估的，这种积极影响得到了改善的组织病理学发现和改善的空间记忆的支持。AGO显示出强大的控制BACE1活性和控制海马淀粉样β（Aβ）沉积的能力。此外，它改善了神经元的存活,神经可塑性，通过提高BDNF水平并促进其有利作用以及通过增强pTrkB表达来实现和神经发生。此外,它上调了类似于突触素I的突触前和突触后神经可塑性生物标志物，突触素,PSD-95此外，AGO对具有A型重复序列（SorLA）途径的Sortilin相关受体具有调节作用，并调节了自噬。值得注意的是，通过施用PD98059aMEK/ERK途径抑制剂（0.3mg/kg/天，i.p.,7天）。总之,AGO给药通过调节ERK/SorLA/BDNF/TrkB信号通路与其调节自噬过程的能力，显着改善与LPS给药相关的记忆和学习障碍。
