ABSTRACT
The multifactorial nature of Alzheimer's disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD-associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE-induced ß-amyloid peptide (Aß) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL-NH2 ) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC50 value against hAChE reported for a peptide (0.99±0.02â µM) and inhibited 94.2 %±1.2 of AChE-induced Aß aggregation at 10â µM. Furthermore, it inhibited hBChE (IC50 , 15.44±0.91â µM), showed no inâ vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe2+ chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Humans , Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Structure-Activity Relationship , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Alzheimer Disease/drug therapyABSTRACT
Natural products represent a rich source of bioactive compounds that have been historically used to obtain substances with great medicinal potential. The skin of anuran amphibians is a rich source of compounds with a wide range of biological activity. Alzheimer's disease (AD) is a complex disease associated with all kind of different pathways, making their simultaneous modulation necessary. Nowadays anti-AD treatments are focused on enzymatic inhibitors. Here in we report the activity of skin extracts from nine species from Argentina, belonging to three anuran families, as inhibitors of AChE, BChE and MAO-B enzymes. The extracts also showed antioxidant activities, acting as multi-target on four important pathways of AD.
Subject(s)
Alzheimer Disease/drug therapy , Amphibians/metabolism , Skin/chemistry , Acetylcholinesterase/metabolism , Animals , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/pharmacology , Peptides/pharmacologyABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia, characterized by loss of selective neuronal and normal brain functions. Every year, ten million new cases are diagnosed worldwide. AD is a complex disease associated with all kind of different pathways, making their simultaneous modulation necessary. Nowadays anti-AD treatments are focused on enzymatic inhibitors. The study of the amphibians' skin had acquired great importance in the fields of biology and human health and represents an attractive and novel source for natural compounds with high potential in the development of new drugs. The present work exhibits the power of amphibian skins as a source of bioactive compounds. Herein we report the activity of extracts of two species from Hylidae family (H. cordobae and P. minuta) as reversible inhibitors of acetylcholinesterase and butyrylcholinesterase enzymes. Furthermore, the extracts inhibit MAO-B enzyme and showed antioxidant activities, acting on four important pathways of AD.