Dissertation
EVALUATION OF SMALL MOLECULE HGF AGONISTS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
Doctor of Philosophy (PhD), Washington State University
01/2017
Handle:
https://hdl.handle.net/2376/112120
Abstract
Neurodegenerative diseases are marked by a loss of neurons and/or their connections in the central nervous system leading to cognitive and/or motor dysfunction. Treatments for neurodegenerative diseases including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), are currently limited and do not significantly alter disease progression. Improved treatments are necessary to reduce the 250 billion dollar annual price tag for the care of people with neurodegenerative diseases in the United States and to improve the quality of life for these patients and their families. Neurotrophic factors that enhance neuroprotection and neuroregeneration are promising treatment targets for neurodegenerative diseases. Despite their proven efficacy, neurotrophic factor based treatments have been limited by problems with delivery and cost of producing the factors. Small molecule agonists of neurotrophic factors provide a potential solution to these problems as these molecules can be engineered to freely pass the blood brain barrier and can be relatively inexpensive to produce. In the following studies a family of small molecule agonists of the neurotrophic factor hepatocyte growth factor (HGF) were evaluated in animal disease models of Parkinson’s, Alzheimer’s, and ALS. The compound PRK-102 was tested in the 6-hydroxy dopamine model of Parkinson’s where it reversed the movement deficits inherent to the model. PRK -102 also had positive impacts on dopaminergic neuron health and downstream synaptic connectivity. The lead Alzheimer’s compound NDX-1001 was evaluated in two models of Alzheimer’s, an aged rat model and a scopolamine induced amnesia model. In both cases treatment with NDX-1001 resulted in improved spatial learning in the Morris water maze and enhanced persistence of the learning response. MM-201 was evaluated in the mutant superoxide dismutase 1 ALS mouse model. Mixed results were obtained with this compound but treatment was connected to increased lower motor neuron survival. The results of these studies suggest that HGF agonists may represent viable treatments for neurodegenerative diseases and should be further evaluated for that purpose. Additionally, these or related compounds should be assessed in other diseases or injuries that may positively impacted by activation of the HGF/Met system.
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Details
- Title
- EVALUATION OF SMALL MOLECULE HGF AGONISTS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
- Creators
- Jewel Chantale LeValley
- Contributors
- Joseph Harding (Advisor)Lisa Gloss (Committee Member)Cliff Berkman (Committee Member)Michael Konkel (Committee Member)Michael Sardinia (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 144
- Identifiers
- 99900581513701842
- Language
- English
- Resource Type
- Dissertation