Promising tacrine/huperzine A- based dimeric AChE inhibitors for neurodegenerative disorders: from relieving symptoms to modifying diseases through multi-target.

Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease, are devastating diseases in the elderly world, which are closely associated with progressive neuronal loss induced by a variety of genetic and environmental factors. Unfortunately, currently available treatments for neurodegenerative disorders can only relieve the symptoms, but not modify the pathological processes. Over the past decades, our group by collaborating with Yuan-Ping Pang and Paul R. Carlier, has developed three series of homo/hetero dimeric acetylcholinesterase (AChE) inhibitors derived from tacrine and/or huperzine A. The representative dimers bis(3)-Cognitin (B3C), bis(12)-hupyridone (B12H), and tacrine(10)-hupyridone (A10E) might possess disease-modifying effects through the modulation of N-methyl-D-aspartic acid (NMDA) receptors, the activation of myocyte enhancer factor 2D (MEF2D) gene transcription, and the promotion of neurotrophic factor secretion. In this review, we summarize that the representative dimers, such as B3C, provide neuroprotection against a variety of neurotoxins via multiple targets, including the inhibitions of NMDA receptor with pathological-activated potential, neuronal nitric oxide synthase (nNOS), and β-amyloid cascades synergistically. More importantly, B3C might offer disease-modifying potentials by activating MEF2D transcription, inducing neuritogenesis, and promoting the expressions of neurotrophic factors in vitro and in vivo. Taken together, the novel dimers might provide synergistic disease-modifying effects, proving that dimerization might serve as one of the strategies to develop new generation of therapeutics for neurodegenerative disorders.