Abstract/Details

Regulation of effector pathways involved in protection from NMDA receptor-induced excitotoxicity in a mouse model of Huntington's disease


2005 2005

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Abstract (summary)

I started this thesis with the hypothesis that Huntington's disease is the result of an increased NMDAR-induced excitotoxicity resulting from long term changes in NMDAR effector pathways and that the neuroprotective agent nicotine would delay toxicity, symptoms and premature death. Many drugs reported to have neuroprotective activity have been shown to decrease symptoms and/or prolong life in mouse models of Huntington's disease. We show in chapter 2 that oral nicotine treatment, reported to be neuroprotective in many other in vivo models to be discussed later, was ineffective in producing significant reduction of symptoms or prolonging life in a mouse model of Huntington's disease. Since the neuroprotective agent nicotine had no effect and the mouse models of Huntington's disease show little neuronal death, we studied the neuronal death associated with NMDA receptor-induced excitotoxicity in a mouse model of Huntington's disease. Other transgenic mouse models have shown decreases, increases, or no effect with respect to NMDA receptor-induced excitotoxicity. In Chapter 3, we report protection from NMDA receptor-induced excitotoxicity in the striata of symptomatic N171-82Q mice, a model of Huntington's disease in which an N-terminal portion of the mutant huntingtin protein containing the extended polyglutamine region associated with the disease is expressed. Chapter 4 and 5 examine the regulation of known effector pathways of NMDA receptor excitotoxicity that may be responsible for the protection observed in the N171-82Q mouse model. We observe decreases in proteins of the neuronal nitric oxide synthase pathway. We also observe decreases in dopamine D1 receptors with a decrease in the associated phosphorylation of the NR1 subunit of the NMDA receptor and an increase in membrane-association of the antiapoptotic phosphatidylinositol-3 kinase, which was recently reported to compete with dopamine D1 receptors for a binding site on NR1. All of these changes would be predicted to protect these neurons from NMDA receptor excitotoxicity. A modified hypothesis is that the “protective” protein changes affecting the two primary inputs to the striatum, glutamatergic and dopaminergic, may be causing a functional deficit responsible for some of the symptoms associated with the disease.

Indexing (details)


Subject
Pharmacology;
Neurons;
Toxicity;
Rodents;
Huntingtons disease
Classification
0419: Pharmacology
Identifier / keyword
Health and environmental sciences; Effector; Excitotoxicity; Huntington's disease; NMDA receptor-induced
Title
Regulation of effector pathways involved in protection from NMDA receptor-induced excitotoxicity in a mouse model of Huntington's disease
Author
Jarabek, Bryan R.
Number of pages
129
Publication year
2005
Degree date
2005
School code
0544
Source
DAI-B 66/03, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542055317, 0542055317
Advisor
Wolfe, Barry B.
University/institution
Georgetown University Medical Center
University location
United States -- District of Columbia
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3168548
ProQuest document ID
305394644
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305394644/abstract
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