Abstract:

Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers. Currently available drugs target symptomatic relief rather than suppressing, ceasing or repairing the devastating neural damages. For Alzheimer’s disease, there are two classes of procognitive compounds that are approved as a treatment of the disease. Acetylcholinesterase (AChE) inhibitors, such as tacrine, donepezil, galantamine and rivastigmine, inhibit the hydrolysis of acetylcholine and elevate the acetylcholine neurotransmitter level. The other class of drug is N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, intended to suppress ?-amyloid induced excitotoxicity. These compounds have produced only modest improvements in cognitive and behavioral symptoms in some Alzheimer’s patients. Thus, tremendous efforts are being made to discover and develop more effective treatments for Alzheimer’s disease. In the midst of the intense investigation for new treatments, there have been increasing effort to understand the cellular effects of the existing nootropic compounds on neurogenesis and neuritogenesis, a central process for the formation of neural networks during brain plasticity and (re)growth, to determine their potential for molding neuroarchitecture. Interestingly, studies have shown that selective procognitive compounds indeed possess such properties. We have recently shown that an AChE inhibitor donepezil can significantly promote neurite outgrowth in a primary cortical culture system. The cellular effects of AChE inhibitors conceivably include stimulation of neurogenesis, because cholinergic receptors are expressed on neuronal progenitors and are coupled to cell proliferation. However, the actual molecular targets of donepezil that promotes neuritogenesis may differ from AChE in light of the lack of effect of tacrine in our study. Donepezil is known to have various other targets in addition to AChE. In particular, donepezil binds sigma1 receptors with high affinity at a low nanomolar range in vitro and behave as an effective sigma1 receptor agonist. Neuroprotective effects of donepezil have been reported to involve a sigma1 interaction in a mouse model and in rodent cortical culture. The authors have reported that donepezil and sigma1 receptor agonist Pre-084 provide a complete neuroprotection in mice treated with β-amyloid peptide 25–35 while only a partial neuroprotection can be achieved with AChE inhibitor tacrine. Furthermore, pre-administration of the sigma1 receptor antagonist BD1047 or in vivo antisense probe treatment blocks the memory-enhancing effect of donepezil. These studies suggest that the procognitive and neuroprotective activities of donepezil are at least partially mediated by sigma1 receptor.