Lian Wenwen, Jia Hao, Xu Lvjie, Zhou Wei, Kang De, Liu Ailin, Du Guanhua
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Aging Neurosci. 2017 Dec 8;9:409. doi: 10.3389/fnagi.2017.00409. eCollection 2017.
D-galactose has been reported to accelerate senescence in rodents, accompanied by a decline in learning and memory. We used a model of D-galactose-induced amnesia for the efficacy evaluation and pharmacologic studies of active compounds against Alzheimer's disease (AD). DL0410 is a potent inhibitor against acetylcholinesterase (AChE) and, in the present study, the effect of DL0410 was evaluated in this model. We found that DL0410 could significantly improve the learning and memory of D-galactose induced aging mice in a series of behavioral tests: novel-object recognition test, nest-building test, Morris water maze test and step-through test. Pharmacologic studies were conducted from several aspects: the cholinergic system, mitochondrial respiration, oxidative stress, neuroinflammation, apoptosis and synaptic loss. The acetylcholine level and AChE activity were not altered by D-galactose but were slightly affected by DL0410 in the brain. DL0410 could significantly improve decreased mitochondrial respiration in the NADH chain and FADH chain, and protect mitochondrial ultrastructure. DL0410 reduced the accumulation of advanced glycation end products (AGEs) and malondialdehyde (MDA) and increase the total antioxidant capability of the brain via an increase in activity of catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD). RAGE expression was inhibited by DL0410, followed by the decreased activation of astrocytes and microglia. Subsequent phosphorylation of NF-κB was also reversed by DL0410, with lower expression of cyclooxygenase-2 (COX2) and iNOS. With respect to apoptosis, the activation of caspase 3 and cleavage of PARP were downregulated significantly by DL0410, after the inhibition of phosphorylation of JNK induced by inflammation and oxidative stress. Synaptic protection by DL0410 was also demonstrated. These data suggest that mitochondrial protection has a primary role in the ameliorating effect of DL0410 on the impaired learning and memory, oxidative stress, inflammation, apoptosis and synaptic loss induced by D-galactose. DL0410 is a promising candidate for the treatment of aging-related AD, and this study lays an important foundation for its further research and development.
据报道，D-半乳糖可加速啮齿动物衰老，并伴有学习和记忆能力下降。我们使用D-半乳糖诱导的失忆模型，对活性化合物抗阿尔茨海默病（AD）的疗效进行评估和药理研究。DL0410是一种有效的乙酰胆碱酯酶（AChE）抑制剂，在本研究中，我们在该模型中评估了DL0410的作用。我们发现，在一系列行为测试中，DL0410可显著改善D-半乳糖诱导的衰老小鼠的学习和记忆能力：新物体识别测试、筑巢测试、莫里斯水迷宫测试和穿梭箱测试。从几个方面进行了药理研究：胆碱能系统、线粒体呼吸、氧化应激、神经炎症、细胞凋亡和突触丧失。D-半乳糖未改变乙酰胆碱水平和AChE活性，但DL0410对大脑有轻微影响。DL0410可显著改善NADH链和FADH链中线粒体呼吸的降低，并保护线粒体超微结构。DL0410通过增加过氧化氢酶、谷胱甘肽过氧化物酶（GPx）和超氧化物歧化酶（SOD）的活性，减少晚期糖基化终产物（AGEs）和丙二醛（MDA）的积累，并提高大脑的总抗氧化能力。DL0410抑制RAGE表达，随后星形胶质细胞和小胶质细胞的激活减少。DL0410还可逆转随后的NF-κB磷酸化，降低环氧合酶-2（COX2）和诱导型一氧化氮合酶（iNOS）的表达。关于细胞凋亡，在抑制炎症和氧化应激诱导的JNK磷酸化后，DL0410显著下调caspase 3的激活和PARP的裂解。DL0410对突触的保护作用也得到了证实。这些数据表明，线粒体保护在DL0410改善D-半乳糖诱导的学习和记忆受损、氧化应激、炎症、细胞凋亡和突触丧失方面起主要作用。DL0410是治疗与衰老相关的AD的有希望的候选药物，本研究为其进一步研发奠定了重要基础。
