Investigating Increased Glutamate Transporter EAAT2 Function as a Potential Therapeutic Approach for Gulf War Illness
Abstract
Summary and Purpose: Cognitive difficulties and mood deficits are the most ubiquitous among the various symptoms of Gulf War Illness (GWI). It is widely believed that these clinical symptoms are linked to a combination of exposures encountered by the Service personnel. Literature has indicated that chronic exposure to GWI-related chemicals, such as pyridostigmine (an anti-nerve gas drug) and permethrin (an insecticide), and stress causes dyshomeostasis of glutamatergic system in the hippocampus, which may be linked to memory and mood deficits. The purpose of this project is to investigate the glutamatergic system in the hippocampus of mice after chronic exposure to GWI-related chemicals and stress and also to investigate if increased glutamate transporter EAAT2 expression by a novel brain-penetrant small molecule, which was developed in our lab, can normalize the dyshomeostasis of the glutamatergic system and subsequently improve cognitive and mood deficits. What type of patients will it help and how will it help them? Cognitive and mood impairments are the common symptoms for GWI patients. If the outcomes of the proposed studies show that enhanced glutamate transporter EAAT2 expression and function is a potential therapeutic approach for GWI, then our small molecule may have potential for treatment of large population of GWI. What are the potential clinical applications, benefits, and risks? The clinical application would be to improve cognitive functions and ameliorate depression/anxiety symptoms with the benefit of improving quality of life. The risks for our compounds have yet to be formally determined, though our studies have found no dose-limiting toxicity in rodents. What is the projected time it may take to achieve a patient-related outcome? We are currently developing our small molecules for human use. If successful, we hope to submit an Investigational New Drug (IND) application by the end of 2018. Human safety trials could begin after the IND application is approved. What are the likely contributions of this study in advancing the field of GWI research? The likely contributions of this study are determining (1) if dysfunction of the glutamatergic system in the hippocampus plays a role in GWI, (2) if enhanced EAAT2 expression and function is a potential therapeutic approach for GWI, and (3) if our small molecules have potential for treatment of GWI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610560
Entities
People
- Chien-liang Lin
Organizations
- Ohio State University
- United States Army