Glycolysis Therapy for Gulf War Illness
Abstract
Overarching Challenge: This project proposes to investigate a delayed (10 and 15 months) glycolysis inhibition treatment for GWI using magnetic resonance imaging (MRI), behavior, and neuropathology techniques for testing a breakthrough drug therapy for GWI. This application is consistent with the goals of the FY20 GWIRP Idea Award, which is intended to support exploratory, high-risk/high-reward research to develop effective treatments for GWI. Nearly 40% of 700,000 Veterans who served in the Persian Gulf War are diagnosed with Gulf War Illness (GWI), a chronic multi-symptom illness that affects peripheral and central systems. Cognitive and mood impairments are among the conspicuous brain-related symptoms in GWI Veterans and in animal models of GWI. Currently there are no proven treatments to provide relief to these sufferers. Therefore, it is critical to find the most efficacious treatments for GWI. Experimental models in animals replicate features of GWI. Consistent with Veterans with GWI symptoms, a rat model showed that concurrent exposure to the GWI chemicals PB (pyridostigmine bromide), DEET, and PM (permethrin) for 4 weeks causes GWI-like neurological features including memory and mood impairments. Such peripheral and central neurological and memory deficits were associated with significant neuronal damage and chronic neuroinflammation. These validated rat models provide valuable tool for development treatments for GWI, especially neurological drugs. Objective and Rationale: Our main goal of this project is to rapidly evaluate the ability of delayed therapy with glycolysis inhibitors 2-deoxyglucose (2-DG) and lonidamine for comprehensive management of GWI, targeting peripheral, sensorimotor, cognitive and central deficits of GWI in a chronic rat model of GWI using MRI, behavioral and neuropathological techniques. The proposed delayed therapy (10 months = human 25 years!) is designed to closely match 25 years that many GWI Veterans have had GWI. The glycolytic pathway represents a practical target for GWI intervention because excessive glycolysis may be involved in key signs such as muscular pain, fatigue, sleep and memory difficulties. Glucose utilization and mitochondrial defects increase following muscular and neuronal injury. 2-DG (FDA-approved), lonidamine and bromopyruvate inhibit the glycolysis pathway in muscle and nerve cells and thus represents a radically new therapy for managing multi-symptom GWI. The key emphasis of this project is to generate strong “proof-of-efficacy” of one lead drug therapy in GWI, which will provide baseline data for immediate clinical trials. 2-DG is an orally active, repurposed drug with a great safety record. Thus, we will test the promising protective effect of three lead drugs in a rat model of GWI under three aims: Aim 1: To test the protective efficacy of 2-DG and glycolytic inhibitors against GWI agent-induced neuromuscular and brain damage using MRI in a rat model reminiscent of human GWI. Aim 2: To test the efficacy of 2-DG and glycolytic inhibitors against GWI agent-induced peripheral and central deficits. AIM 3: To determine the efficacy of 2-DG and glycolytic inhibitors against GWI-related neuropathological changes. We will employ a well-validated rat model of chronic GWI by Shetty lab. We propose to use MRI to monitor the biomarkers of GWI and treatment efficacy. Rats will be randomly assigned to control group or GWI groups (N=20) receiving GWI chemicals PB, PM, and DEET. The test drugs (2-DG, lonidamine or bromopyruvate) will be given for 4 weeks as delayed therapy (10 and 15 months later), which is equivalent to 25 and 35 years of post-GWI period. Brain pathology will be measured by MRI scanning of animals. The outcome of the project will provide: (i) critical data to uncover the MRI biomarkers in chronic GWI model; (ii) establish the efficacy of the glycolysis inhibition therapy in GWI for attenuating peripheral, cognitive and neurological deficits; (i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110311
Entities
People
- Samba Reddy
Organizations
- Texas A&M University
- United States Army