Preclinical evidence of neuroprotection by cholinesterase inhibitors.

The protection of neurons from damage and death in neurodegenerative disorders, such as Alzheimer disease (AD), is a major challenge for neuroscientists in the 21st century. The amyloid beta-protein plays an important role in the degenerative process of the disease and increases the vulnerability of cultured cortical neurons to glutamate neurotoxicity. Glutamate may, therefore, play an important role in amyloid beta-protein-induced cytotoxicity in the cerebral cortex. Results show that cholinesterase inhibitors such as donepezil protect cortical neurons against glutamate neurotoxicity via alpha4beta2 and alpha7 nicotinic acetylcholine receptors at least partly by inhibiting the process of apoptosis. Donepezil also protects against ischemic insults such as those seen in vascular dementia; however, this does not seem to be mediated by nicotinic receptors. This review summarizes data that suggest donepezil possesses neuroprotective actions in addition to amelioration of cognitive deficits by inhibition of acetylcholinesterase.