DL0410 ameliorates cognitive disorder in SAMP8 mice by promoting mitochondrial dynamics and the NMDAR-CREB-BDNF pathway  

作　　者：Wen-wen Lian Wei Zhou Bao-yue Zhang Hao Jia Lv-jie Xu Ai-lin Liu Guan-hua Du 

机构地区：[1]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 100050,China [2]Department of Pharmacy,China-Japan Friendship Hospital,Beijing 100029,China

出　　处：《Acta Pharmacologica Sinica》2021年第7期1055-1068,共14页中国药理学报（英文版）

基　　金：The study was supported by the National Great Science Technology Projects(2014ZX09507003-002);the Drug Innovation Major Project(No.2018ZX09711001-003-002);the CAMS Initiative for Innovative Medicine(CAMS-IZM)(2016-IZM-3-007);the Beijing Natural Science Foundation(7192134,7204303);and the National Natural Science Foundation of China(81673480).

摘　　要：Alzheimer’s disease (AD) is a worldwide problem and there are no effective drugs for AD treatment. Previous studies show that DL0410 is a multi-target, anti-AD agent. In this study, we investigated the therapeutic effect of DL0410 and its action mechanism in SAMP8 mice. DL0410 (1−10 mg·kg−1·d−1) was orally administered to 8-month-old SAMP mice (SAMP8) for 8 weeks. We showed that DL0410 administration effectively ameliorated the cognitive deficits in the Morris water maze test, novel object recognition test, and nest building test. We revealed that DL0410 dose-dependently increased the expression levels of the mitochondrial proteins (PGC-1α, Mitofusin 2, OPA1, and Drp1), and subsequently ameliorated the processes of mitochondrial biosynthesis, fusion, and fission in the cortex and hippocampus of SAMP8 mice. Furthermore, DL0410 administration promoted the expression of synaptic proteins (synaptophysin and PSD95) in the brain of SAMP8 mice, and upregulated the protein phosphorylation in NMDAR- CAMKII/CAMKIV-CREB pathway responsible for the synaptic plasticity. DL0410 administration dose-dependently increased the expression of BDNF and TrkB, and the neurotrophic effect was mediated via the ERK1/2 and PI3K-AKT-GSK-3β pathways. DL0410 administration upregulated Bcl-2, increased the Bcl-2/Bax ratio and the level of caspase 3 and PARP-1, alleviating neuronal apoptosis. We proposed that the NMDAR-CREB-BDNF pathway might establish a positive feedback loop between synaptic plasticity and neurotrophy, with CREB at the center. In summary, DL0410 promotes synaptic function and neuronal survival, thus ameliorating cognitive deficits in SAMP8 mice via improved mitochondrial dynamics and increased activity of the NMDAR-CREB- BDNF pathway. DL0410 is a promising candidate to treat aging-related AD, and deserves more research and development in future.

关 键 词：DL0410 synapse plasticity NEUROTROPHY mitochondrial dynamics CREB 

分 类 号：R285.5[医药卫生—中药学]