Fascaplysin Derivatives Are Potent Multitarget Agents against Alzheimer’s Disease: <i>in Vitro</i> and <i>in Vivo</i> 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 <i>Fascaplysinopsis bergquist</i> 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 <i>in vitro</i>. Compounds <b>2a</b> and <b>2b</b>, the two most powerful compounds <i>in vitro</i>, were further selected to evaluate their cognitive-enhancing effects in animals. Both <b>2a</b> and <b>2b</b> could ameliorate cognitive dysfunction induced by scopolamine or Aβ oligomers without affecting locomotor functions in mice. We also found that <b>2a</b> and <b>2b</b> could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Aβ-induced tau hyperphosphorylation <i>in vivo</i>. Most importantly, pharmacodynamics studies suggested that <b>2b</b> 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.