Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent.
Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular beta-amyloid precursor protein, and secreted beta-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower beta-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.
Greig
Nigel H
NH
Laboratory of Neurosciences and Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA. greign@grc.nia.nih.gov
Utsuki
Tadanobu
T
Ingram
Donald K
DK
Wang
Yue
Y
Pepeu
Giancarlo
G
Scali
Carla
C
Yu
Qian-Sheng
QS
Mamczarz
Jacek
J
Holloway
Harold W
HW
Giordano
Tony
T
Chen
DeMao
D
Furukawa
Katsutoshi
K
Sambamurti
Kumar
K
Brossi
Arnold
A
Lahiri
Debomoy K
DK
D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012694:Serine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D012694:Serine; D002091:Butyrylcholinesterase; D000109:Acetylcholine