Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: in Vitro and in Vivo Evidence

Abstract

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a β-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and β-amyloid (Aβ) to produce anti-AD properties. In this study, a series of fascaplysin derivatives were synthesized. The cholinesterase inhibition activities, the neuronal protective effects, and the toxicities of these compounds were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in vitro, were further selected to evaluate their cognitive-enhancing effects in animals. Both 2a and 2b could ameliorate cognitive dysfunction induced by scopolamine or Aβ oligomers without affecting locomotor functions in mice. We also found that 2a and 2b could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Aβ-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood–brain barrier and be retained in the central nervous system. All these results suggested that fascaplysin derivatives are potent multitarget agents against AD and might be clinical useful for AD treatment.

Direct investigation of current transport in cells by conductive atomic force microscopy

“…The green fluorescence can be induced by fluorescein. Thus the FDA positive (green stained cells) and negative cells are live and dead cells, respectively (Pan et al, 2019). All the cells in Figure 1(E) were shown green, which indicates that the cultured cells are all live cells definitely.…”

Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer’s Disease

“…Based on molecular modeling studies, 9-methylfascaplysin ( Figure 5 g), a fascaplysin derivative, was synthesized [ 60 , 61 ]. Docking analyses suggested that the binding to AChE active site differs from fascaplysin, which only binds to the peripheral anionic site.…”

“…Docking analyses suggested that the binding to AChE active site differs from fascaplysin, which only binds to the peripheral anionic site. The referred derivative possibly binds also to the catalytic site residue leading to an enhanced AChE inhibitory activity [ 60 ].…”

“…Studies performed in vitro also showed its potential to activate antioxidant enzymes and thus, to produce neuroprotective effects against ROS. 9-Methylfascaplysin crossed the BBB in mice, preventing cognitive damages through the inhibition of AChE in the hippocampus, without causing severe neurotoxicity [ 60 ].…”

“…Studies in vitro and in vivo suggested that this molecule can prevent cognitive dysfunction, decrease neuroinflammation, and reduce tau hyperphosphorylation, but further investigations regarding its safety profile are required [ 60 ]. Fascaplysin derivatives can become a new class of potential multi-target drugs for AD.…”