Current concepts on selected plant secondary metabolites with promising inhibitory effects against enzymes linked to Alzheimer's disease.

Alzheimer's disease (AD) has become one of the deadliest diseases for human beings with special incidence in elderly population. It is a progressive neurodegenerative disease and the most prevalent cause of dementia. The neuropathology of AD has not been fully elucidated yet, however, cholinergic hypothesis is the most accepted theory nowadays, resulting from the cholinergic deficit emerging in the brains of AD patients. Shortage of the neurotransmitters, acetylcholine and butyrylcholine has been demonstrated, and therefore, inhibition of the enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that break down acetylcholine and butyrylcholine has become a standard approach for AD treatment. However, cholinesterase inhibitors are only effective in symptomatic treatment and have no ability to impede the disease. The pathogenesis of AD is highly complex and another hypothesis is the formation of amyloid plaques containing beta-amyloid peptide, which causes neurolesions in the brains of AD patients. Beta-amyloid peptide is generated after the sequential cleavage of amyloid precursor protein, especially by the beta- and gamma-secretase in the amyloidogenic pathway. The secretases involved in the processing of amyloid precursor protein are of particular interest and, consequently, the inhibition of secretase enzyme family of protease type has become another desired treatment strategy for AD. On the other hand, medicinal plants are attractive sources for drug research and development as they produce chemically-varying molecules with preferred biological activities. The aim of this article is to review the available data on selected inhibitors from plant secondary metabolites with emphasis on cholinesterase, prolyl endopeptidase, and secretase enzyme families as being the current treatments of AD.

An overview on natural cholinesterase inhibitors--a multi-targeted drug class--and their mass production.

Cholinesterase enzyme family consisting of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) is important in pathogenesis of Alzheimer's disease (AD), explained by "cholinergic hypothesis". Accordingly, deficiency of the neuromediator called "acetylcholine" excessive amount of BChE has been well-described in the brains of AD patients. Consequently, cholinesterase inhibition has become one of the most-prescribed treatment strategies for AD. In fact, cholinesterase inhibitors have been also reported for their effectiveness in some other diseases including glaucoma, myasthenia gravies, as well as Down syndrome, lately. They play a role in the action of mechanism of insecticidal drugs such as carbamate derivatives as well as nerve gases such as malathion and parathion. All these utilizations can make them a multi-targeted drug class putting a special emphasis on AD therapy in the first place. Several inhibitors of cholinesterases with synthetic and natural origins are available in drug market; however, the reasons including side effects, relatively low bioavailability, etc. limit their uses in medicine and there is still a great demand to discover new cholinesterase inhibitors. Galanthamine, an alkaloid derivative isolated from snowdrop (Galanthus nivalis L.), is the latest anticholinesterase drug used against AD. Huperzine A, isolated from Huperzia serrata (Thunb.) Trev. is the most-promising drug candidate with potent anticholinesterase effect and it is a licensed anti-AD drug in China. In this review, a short introduction will be given on known cholinesterase inhibitors and, then, galanthamine and huperzine A will be covered in regard with their cholinesterase inhibitory potentials and mass productions by organic synthesis and in vitro culture techniques.