N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer's disease with neuroprotective effects.

Alzheimer's disease (AD) has become a serious threat to the developed nations with burgeoning patients and annual costs on health care system in modern society. Neuroinflammation, as one of the specific biochemical factors in the progress of neurodegeneration diseases, performs a crucial role in the pathogenesis and development of AD. Therefore, it is of great significance to develop effective anti-neuroinflammatory strategies for the treatment of AD. N-salicyloyl tryptamine derivatives were previously reported and demonstrated that possessed great potential anti-neuroinflammatory effects and favorable blood-brain barrier (BBB) permeation. Herein, a series of novel N-salicyloyl tryptamine derivatives were synthesized and their anti-AD potential was evaluated both in vitro and in vivo. Among them, L7 performed well anti-neuroinflammatory effects and excellent neuroprotective effects, as well as little toxicity. To lucubrate its potential for the treatment of AD, behavior tests including morris water maze (MWM), eight-arm radial maze, open field test and novel object recognition (NOR) test were carried out and the results showed that L7 could remarkably improve Aβ-induced cognitive impairment. Moreover, the mechanism of action of L7 on improving Aβ-induced AD was preliminarily investigated, and the results uncovered that the neuroprotective effects of L7 was might exerte via intervening Aβ-induced pyroptosis through NLRP3-caspase-1-GSDMD axis and ameliorating neuronal apoptosis by mitochondrial apoptosis pathway. Besides, the distribution of Aβ plaques in brain tissues were detected by immunohistochemical (IHC) assay and the results indicated that L7 could significantly attenuate the deposition of Aβ plaques in the brain.