Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders: an update

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders. If more effective therapies than the ones currently available are not developed that either prevent AD or other neurodegenerative or block progression of the diseases in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Besides the neuropathologic hallmarks of the diseases, namely neurofibrillary tangles and AD neuritic plaques, the disease is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, particularly affecting cholinergic neurons in basal forebrain. AD and other forms of dementia could be treated by the use of agents which restore the level of acetylcholine through inhibition of both two major forms of cholinesterase: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, the inhibition of AChE holds a key role not only to enhance cholinergic transmission in the brain but also to reduce the aggregation of beta-amyloid and the formation of the neurotoxic fibrils in AD. Following this view, in recent years, an increased interest has emerged directed to finding drugs able to inhibit both of these events. This review summarizes and highlights recent advances in current knowledge on natural products as cholinesterase inhibitors and how these compounds have also served as the starting points for semi-synthetic analogs with improved properties.