Neurosteroid Therapy for Gulf War Illness
Abstract
This project proposes to investigate a delayed (10 and 15 months) neurosteroid treatment for GWI using magnetic resonance imaging (MRI), behavior, and neuropathology techniques for testing the new drug efficacy. This application is consistent with the goals of the FY18 Gulf War Illness Research Program Investigator-Initiated Focused Research Award (Discovery Tier). It seeks funds for a Tier 1 Award, which is intended to support exploratory, high-risk/high-reward research with the potential to yield new approaches for diagnosis or treatment of GWI. Over 40,000 Veterans who served in the 1991 Gulf War have chronic multi-symptom illness that defines Gulf War Illness (GWI). Cognitive and mood impairments are among the conspicuous brain-related symptoms in GWI Veterans and in animal models of GWI. Although several potential causes have been proposed for GWI, epidemiological and other investigations suggest that GWI in Veterans is linked to a combination of chemical exposures encountered by Service personnel during the Gulf War. The chemicals included pyridostigmine bromide (PB), DEET (a mosquito repellent), and permethrin (PM, an insecticide). However, presently there are no proven treatments to provide relief to these sufferers. Therefore, it is critical to find 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 GWI-related chemicals PB, DEET, and PM 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. Our main goal of this project is to develop a safe and broad-spectrum treatment to reduce neuronal damage and enhance the neuropsychiatric wellness in GWI Veterans. This project is designed to test the delayed (10 and 15 months after GWI) therapeutic efficacy of neurosteroid therapy with ganaxolone in the rat model of chronic GWI using MRI and behavioral techniques. The proposed delayed therapy (15 months = human 35 years) falls beyond 25 years that many GWI Veterans have had GWI. Ganaxolone (GX) is a synthetic neurosteroid that promotes tonic inhibition in the brain. The primary emphasis is to utilize the MRI for evaluating the efficacy of tonic inhibition therapy with GX in GWI. The drug targets a novel mechanism (tonic inhibition) of exceptional clinical impact and application for Veterans suffering from GWI diagnosis. GX is an orally active, repurposed drug with a great safety record. GX is Food and Drug Administration (FDA)-approved for human trials and currently in trials for seizures and chemical neurotoxicity. To date, GX has been tested in 1000 subjects in clinical trials. GX is safe and well-tolerated by oral pills, and also injections. Moreover, this treatment strategy has been shown to be effective for brain illnesses caused by chemical exposures (such as organophosphates and nerve agents), but not yet studied in GWI. Therefore, in this project, we will test the promising protective effect of GX in rat model of GWI under three specific aims: Aim 1: To determine the efficacy of GX against GWI agent-induced brain damage using MRI scanning. Aim 2: To determine the efficacy of GX against GWI agent-induced peripheral, behavioral, and memory deficits. Aim 3: To determine the efficacy of GX against GWI agent-induced neuropathological changes. We will employ standard methods to assess test drug using a well-validated rat model of chronic GWI by the Shetty lab. Rats will be randomly assigned to control group or GWI groups (N=20) receiving GWI-related chemicals PB, PM, and DEET. The test drug ganaxolone (10 mg/kg, sc) will be given for 8 weeks as delayed therapy (10 and 15
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910702
Entities
People
- Doodipala Reddy
Organizations
- Texas A&M University
- United States Army