Neuroprotective Effects and Cognitive Enhancement of Allomargaritarine in 5xFAD Alzheimer's Disease Mice Model

Abstract

Here, we report the results of an investigation of the neuroprotective effects of securinine with tryptamine conjugate-allomargaritarine (2b), previously selected as the leading compound among a wide range of natural derivatives. 2b was synthesized from securinine using various Lewis acids as catalysts. In addition to the antioxidant and cytoprotective properties previously shown for 2b, in this work,<em> in vitro</em> analysis of the biological activity of the compound demonstrated that this conjugate is also able to influence the primary pathogenetic mechanism of Alzheimer's disease - proteinopathy, modulating the homeostasis of β-amyloid peptide. In particular, it was found that 2b is an effective inhibitor of β-secretase 1 - an enzyme responsible for initiating the generation of pathological forms of β-amyloid peptide, as well as directly preventing the pathological aggregation of Aβ<sub>1-42</sub>. As a compound with a promising biological activity profile found <em>in vitro</em>, 2b has also demonstrated excellent neuroprotective effects on the <em>in vivo</em> 5xFAD Alzheimer's disease transgenic mice model. Thus, 2b effectively restored cognitive dysfunction: short-term and long-term episodic and spatial memory, which in the <em>post-mortem</em> studies was also accompanied by a decrease in the number of amyloid deposits and the intensity of oxidative stress in brain samples. These results provide an opportunity to draw a line under years of research on the neuroprotective potential of 2b as a viable therapy for Alzheimer's disease.