Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by dementia, personality changes, and movement disorders. Knowledge of the pathogenesis of neuronal death in HD may lead to insights into the pathogenesis of other dementing illnesses. The striatum is prominently affected in Huntington's disease. Some evidence indicates that striatal damage caused by acute intrastriatal administration of N-methyl-D-aspartate (NMDA) agonists is a good experimental model of HD, implying that excessive NMDA receptor activation is involved in neuronal death in HD. The present model has several drawbacks; 1) controversy over some aspects of the model; 2) limited usefulness as a technique for preclinical evaluation of potential therapies; 3) lack of knowledge about how NMDA receptors might become excessively activated in HD. We have developed a new model of HD utilizing chronic intrastriatal administration of the NMDA agonist quinolinic acid (QA). Our preliminary data indicates that chronic intrastriatal Qa administration is a good experimental model of HD. We propose to further evaluate the consequences of intrastriatal QA administration to demonstrate that chronic QA administration does replicate the histopathology of HD. Our model provides a better means of evaluating potential therapies for HD and we will use this model to test the efficacy of systemically administered NMDA antagonists, co-administered nitric oxide synthase inhibitors, and fetal striatal grafts. Finally, chronic administration will be used to explore a mechanism that might lead to excessive NMDA receptor activation by studying the potential neurotoxic consequences of disrupting striatal energy metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG008671-10
Application #
6267441
Study Section
Project Start
1998-07-01
Project End
1999-05-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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