2004 - Effects Of Diverse Cholinesterase Inhibitors And Memantine On The Amyloid Pathway And Its Implications In Alzheimer’s Disease
Topic: <FONT COLOR=MEDIUMSLATEBLUE>
Therapeutics and Therapeutic Strategies - Therapeutic Strategies, Amyloid-based</FONT>
Debomoy K. Lahiri1,
Jason Bailey1,
George Alley1,
Demao Chen1,
Kumar Sambamurti2,
Nigel Greig3,
1Indiana University School of Medicine, Indianapolis, IN, USA;
2Medical University of South Carolina, Charleston, SC, USA;
3National Institute on Aging, Baltimore, MD, USA. Contact e-mail: dlahiri@iupui.edu
Presentation Number: O3-06-01
Keyword: amyloid precursor protein (APP), cholinesterase inhibitor, memantine
Background:
The deposition of the amyloid beta peptide (Aâ) is believed to trigger a cascade of events leading to the loss of cholinergic neurons and the progressive dementia in Alzheimer's disease (AD).
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A therapeutic strategy for AD is to reduce levels of toxic Aâ, which is generated from a larger Aâ precursor protein (APP) by ‘secretases’. </FONT>
Cholinesterase inhibitors (ChE-Is) and memantine are the only approved FDA drugs for AD.
Herein, we examined the effects of diverse novel ChE-Is and the uncompetitive NMDA receptor antagonist, memantine, on APP levels. <FONT COLOR=FIREBRICK><FONT SIZE=5>
Our results have uncovered different alternative mechanisms of APP regulation by these drugs.</FONT>
Objectives(s):
Our aim was to study both FDA approved drugs, such as
<FONT COLOR=MEDIUMSLATEBLUE>
donepezil,
galantamine,
rivastigmine,
memantine
and emerging drugs,
such as Phenserine
that is a selective acetyl-ChE-I
now in phase III clinical trials.</FONT>
<FONT COLOR=BLACK>Methods:
We tested the compounds in three models: </FONT>
<FONT COLOR=FIREBRICK><FONT SIZE=5>
i) human neuroblastoma cell line,
ii) primary rat fetal cortical neuronal cells and
iii) mice within non-toxic dose range. </FONT>
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In cell culture experiments toxicity and viability were measured by LDH and MTT assays.
Levels of APP and Aâ were measured by Western immunoblotting and sandwich ELISA.
Results:
The aforementioned drugs, including the ChE-Is and memantine, affect APP metabolism in multiple ways. </FONT>
<FONT COLOR=BLUE>
The first group of drugs (e.g., memantine and phenserine) lowered sAPP levels, </FONT>
<FONT COLOR=RED>The second group showed a trend towards an elevated sAPP (e.g., rivastigmine) and </FONT>
<FONT COLOR=STEELBLUE>The third group (e.g., galantamine) insignificantly affected sAPP in terms of APP and Aâ levels. </FONT>
Effects of these drugs on different targets,
such as secretases and
on the 5’-UTR of APP, are also being tested.
<FONT COLOR=MEDIUMSLATEBLUE>
Conclusion:
Characterization of these drugs' actions on APP and Aâ biogenesis demonstrates an amyloid-modifying property,
and such studies should accelerate the
discovery of novel drugs for AD as well
as optimize the use of currently approved drugs.</FONT>
Commercial Relationship:
D.K. Lahiri, Axonyx Specific research activities;
Forest Specific research activities;
Novartis Specific research activities.
OASIS - Online Abstract Submission and Invitation System™ ©1996-2004, Coe-Truman Technologies, Inc.
The only way to reach this link is to go here, bring
up ADVANCED SEARCH and use MEMANTINE as the Key Word.
Abstracts (11 abstracts for Memantine) come up in seperate
windows which do NOT have links available.
I searched for phenserine but could not find
anything under Sessions or Posters
alz.org |
