Alzheimer's disease therapy based on acetylcholinesterase inhibitor/blocker effects on voltage-gated potassium channels.

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder with progressive loss of memory and other cognitive functions. The pathogenesis of this disease is complex and multifactorial, and remains obscure until now. To enhance the declined level of acetylcholine (ACh) resulting from loss of cholinergic neurons, acetylcholinesterase (AChE) inhibitors are developed and successfully approved for AD treatment in the clinic, with a limited therapeutic effectiveness. At present, it is generally accepted that multi-target strategy is potently useful for designing novel drugs for AD. Accumulated evidence reveals that Kv channels, which are broadly expressed in brain and possess crucial functions in modulating the neuronal activity, are inhibited by several acetylcholinesterase (AChE) inhibitors, such as tacrine, bis(7)-tacrine, donepezil and galantamine. Inhibition of Kv channels by these AChE inhibitors can generate neuroprotective effects by either mitigating Aβ toxicity and neuronal apoptosis, or facilitating cell proliferation. These inhibitory effects provide additional explanations for clinical beneficial effectiveness of AChE inhibitors, meaning that Kv channel is a promising candidate target for novel drugs for AD therapy.