Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease.

Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Research Abstract Details 

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Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Abstract Text:

Debomoy K Lahiri,George M Alley,David Tweedie,Demao Chen,Nigel H Greig,

One of the main hallmarks of Alzheimer's disease (AD) is the brain deposition of senile plaques made up of toxic amyloid beta-peptide (Abeta), which is derived from a larger protein called the beta-amyloid precursor protein (APP). Both APP processing and cholinesterase activity are affected in the AD brain, but, yet, cholinesterase inhibitors (ChEI) remain the primary Food and Drug Administration approved drugs for AD within the United States. Herein, we evaluated the effects of two clinically relevant drugs on the APP pathway, which is presumably involved in AD pathogenesis. Specifically, we compared the actions of the classical ChEI physostigmine (PHY) and its analog phenserine (PHE) on neuronal cell viability, on IC50 and on levels of different amyloid proteins. Interestingly, these drugs share the same chemical backbone, inhibit acetylcholinesterase with similar potency, but differentially affect APP processing. PHE treatment decreased levels of APP in the human neuroblastoma cells (p=0.009) whereas PHY showed a similar but less-pronounced trend, which did not attain statistical significance. PHE treatment significantly decreased levels of Abeta in human neuroblastoma cells (p=0.02) whereas PHY showed no significant change under the same conditions. The divergent actions of these two structurally related drugs on the amyloid pathway indicate that the mechanisms underpinning the cholinergic and the amyloid-lowering properties for this class of drugs are independent of each other.

Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Publishing Authors By Initials

DK Lahiri,GM Alley,D Tweedie,D Chen,NH Greig,

For similar heterocyclic compounds: heterocyclic compounds, 1-ring: azoles: pyrroles research abstracts see: heterocyclic compounds: heterocyclic compounds, 1-ring: azoles: pyrroles research

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Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Neuromolecular medicine

VOLUME: 9

Page Numbers: 157-68

Journal Abbreviation: Neuromolecular Med.

ISSN: 1535-1084

DAY: 3

MONTH: 12

YEAR: 2007

Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101135365

Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Keywords Mesh Terms:

KEYWORDS: Pyrroles

MESH TERMS: therapeutic use

Chemical & Substance for Abstract: Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease. Information

Substance Name: Acetylcholinesterase

Registry Number: EC 3.1.1.7

Grant and Affiliation Information for Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease.

AFFILIATION: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dlahiri@iupui.edu

Country: United States

AGENCY: United States NIA

GRANT: AG18884

ACRONYM: AG

MEDLINETA: Neuromolecular Med

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