Yu-Heng Hu,Jie Yang,Yun Zhang,Ke-Chun Liu,Teng Liu,Jie Sun,Xiao-Jing Wang
The work is focused on the design of drugs that prevent and treat Alzheimer’s disease (AD) and its complications. A series of 3–(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 ± 0.011 µM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 ± 0.017 µM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications.
Endoplasmic reticulum (ER) stress-induced neuronal apoptosis is a crucial pathological process of spinal cord injury (SCI). In our previous study, icariin (ICA) showed neuroprotective effects in SCI. However, the relationships between ER stress and ICA in SCI are unclear yet. Therefore, whether ICA could ameliorate SCI via attenuating ER stress was investigated in vitro and in vivo . Adult mice were established SCI model and received vehicle solution or ICA by gavage once per day in vivo . The primary cultured cells were treated with or without thapsigargin (TG), ICA or LY294002 to induce ER stress in vitro . Motor dysfunction, neuronal apoptosis, tissue damage and inhibition of PI3K/AKT pathway were induced by ER stress after SCI. But ICA administration significantly enhanced motor recovery and protected spinal cord tissues against infraction and hemorrhage, etc. post injury. Meanwhile, the expression of ER stress markers ATF6, IRE1α, GRP78, XBP1 and eIF2α was decreased, while the level of p-AKT/AKT was increased by ICA. Furthermore, ICA significantly inhibited the expression of ER stress apoptotic proteins caspase-12, CHOP, Bax/Bcl-2, caspase-9 and caspase-3. Moreover, immunofluorescence double staining indicated that ICA reduced GRP78, CHOP and TUNEL positive neurons following SCI. However, this beneficial effect of ICA was abolished by PI3K/AKT inhibitor LY294002 in vitro . Finally, ICA preserved the ultra-structure of ER by transmission electron microscope histologically. This study suggested that the neuroprotective effect of ICA on motor recovery and neuronal survival was related to attenuating ER stress via PI3K/AKT signaling pathway after SCI.
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