期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 11, 页码 2209-2219出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.04.025
关键词
Andrographolide; Neuroinflammation; Oxidative stress; Neurite outgrowth; mAChRs; Alzheimer's disease
资金
- National Natural Science Funds [81602994]
- Scientific Startup Foundation for Doctors of Northwest AF University [2452015353]
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and remains incurable. Currently, neuronal injury and synapse loss have been considered to be main features in the pathophysiology of AD. Thus, modulation of neuronal survival and neurite outgrowth may represent an efficient strategy for the treatment of AD. Based on the isolates from the traditional medicine Andrographis paniculata, a series of andrographolide analogues were prepared and evaluated for the neuroprotection and neurotrophic activity. Two compounds (3 and 12) could effectively inhibit LPS-induced NO production and iNOS expression as well as proinflammatory cytokines TNF-alpha and IL-6. Moreover, pretreatment with 3 and 12 could protect neurons against microgli-amediated neurotoxicity. Further, H2O2- and 6-OHDA induced neurotoxicity in PC12 cells were also attenuated by the novel 12. Our next study indicated that compounds 1, 4 and 10 promoted NGF-induced neurite outgrowth in PC12 cells, with 10 the most potent. To clarify the underlying mechanisms of active compounds (3, 10 and 12), system pharmacology was employed. The results revealed that muscarinic acetylcholine receptors (mAChRs) may be the main targets of 12 against AD, while thyroid hormone signaling pathway was involved in the mechanisms of 10. These study point to the therapeutic potential of andrographolide analogues against AD.
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