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Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent


Year of Publication:
Contact PI Name:
Nigel H. Greig
Contact PI Affiliation:
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA
Tadanobu Utsuki, Donald K. Ingram, Yue Wang, Giancarlo Pepeu, Carla Scali, Qian-Sheng Yu, Jacek Mamczarz, Harold W. Holloway, Tony Giordano, DeMao Chen, Katsutoshi Furukawa, Kumar Sambamurti, Arnold Brossi, Debomoy K. Lahiri
Primary Reference (PubMED ID):
Funding Source:
Intramural Research Program of the National Institute on Aging
National Institute on Aging (NIA)
Alzheimer's Association
Axonyx Inc.
Study Goal and Principal Findings:

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 longterm 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 β-amyloid precursor protein, and secreted β-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower β-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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Butyrylcholinesterase (BChE)
Therapy Type:
Small Molecule
Therapeutic Agent:
(-)-N1-phenethylnorcymserine (PEC)
Therapeutic Target:
Butyrylcholinesterase (BChE)
Therapy Type:
Small Molecule
Therapeutic Agent:
N8-bisnorcymserine (BNC)
Therapeutic Target:
Butyrylcholinesterase (BChE)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Fischer 344

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
T Maze
Amyloid Precursor Protein (APP)
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
Acetylcholine Release
Butyrylcholinesterase (BChE)
Acetylcholinesterase (AChE)
Long Term Potentiation (LTP)
field Excitatory Postsynaptic Potential (fEPSP)
Drug Concentration-Brain
Drug Concentration-Plasma
Brain t1/2
Plasma t1/2
Target Engagement (Inhibition Butyrylcholinesterase)
Maximum Tolerated Dose (MTD)