DL0410 attenuates oxidative stress and neuroinflammation via BDNF/TrkB/ERK/CREB and Nrf2/HO-1 activation.
Oxidative stress and neuroinflammation have been deeply associated with Alzheimer's disease. DL0410 is a novel acetylcholinesterase inhibitor with potential anti-oxidative effects in AD-related animal models, while the specific mechanism has not been fully clarified. In this study, DL0410 was predicted to be related to the modification of cell apoptosis, oxidation-reduction process, inflammatory response and ERK1/ERK2 cascade by in silico target fishing and GO enrichment analysis. Then the possible protective effects of DL0410 were evaluated by hydrogen peroxide (H2O2)-induced oxidative stress model and lipopolysaccharides (LPS)-induced neuroinflammation model H2O2 decreased the viability of SH-SY5Y cells, induced malondialdehyde (MDA) accumulation, mitochondrial membrane potential (Δψm) loss and cell apoptosis, which could be reversed by DL0410 dose-dependently, indicating that DL0410 protected SH-SY5Y cells against H2O2-mediated oxidative stress. Western blot analysis showed that DL0410 increased the H2O2-triggered down-regulated TrkB, ERK and CREB phosphorylation and the expression of BDNF. In addition, TrkB inhibitor ANA-12, ERK inhibitor SCH772984 and CREB inhibitor 666-15 eliminated the inhibition of DL0410 on MDA accumulation and Δψm loss. Furthermore, DL0410 attenuates inflammatory responses and ROS production in LPS-treated BV2 cells, which is responsible for Nrf2 and HO-1 up-regulation. The present study demonstrates that DL0410 is a potential activator of the BDNF/TrkB/ERK/CREB and Nrf2/HO-1 pathway and may be a potential candidate for regulating oxidative stress and neuroinflammatory response in the brain. Together, the results showed that DL0410 is a promising drug candidate for treating AD and possibly other nervous system diseases associated with oxidative stress and neuroinflammation.
['Zhang|Baoyue|B|', 'Zhao|Jun|J|', 'Wang|Zhe|Z|', 'Xu|Lvjie|L|', 'Liu|Ailin|A|', 'Du|Guanhua|G|']
D000818:Animals D000975:Antioxidants D017209:Apoptosis D001713:Biphenyl Compounds D019208:Brain-Derived Neurotrophic Factor D002460:Cell Line D019295:Computational Biology D017362:Cyclic AMP Response Element-Binding Protein D016207:Cytokines D062126:Databases, Chemical D048049:Extracellular Signal-Regulated MAP Kinases D051547:Heme Oxygenase-1 D006801:Humans D006861:Hydrogen Peroxide D007249:Inflammation D008070:Lipopolysaccharides D008315:Malondialdehyde D008562:Membrane Glycoproteins D053078:Membrane Potential, Mitochondrial D008565:Membrane Proteins D051379:Mice D017628:Microglia D051267:NF-E2-Related Factor 2 D018384:Oxidative Stress D010880:Piperidines D020813:Receptor, trkB D015398:Signal Transduction
DL0410 Oxidative stress Neuroinflammation Alzheimer’s disease Mitochondrial dysfunction