Neurosteroid Therapy for Gulf War Illness

Abstract

Neurosteroid Therapy for Gulf War Illness This pre-application is submitted under the DOD Gulf War Illness Research Program (GWIRP)– Investigator-Initiated Focused Research Award under Discovery Tier. It seeks funds for a Tier 1 (Discovery) 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. This project is designed to test the delayed (10 & 15 months after GWI) therapeutic efficacy of neurosteroid therapy in the rat model of chronic GWI using MRI imaging and behavioral techniques. The proposed delayed therapy (15 months = human 35 years!) falls beyond 25 years that many GWI veterans have had GWI. Since GWI is purportedly caused by exposure to low-level sarin and other chemicals, tonic inhibition-promoting neurosteroids are proposed as effective treatment because they have been shown to be highly efficacious against acute and chronic neurotoxicity caused by nerve agents and organophosphate exposure. This is a logical plan as per the GWI pathophysiology and neurosteroid’s promise as experimental treatment. Our team is poised to lead this project as we have preclinical expertise and experience in GWI models. The Central Hypothesis is that neurosteroids (FDA approved ganaxolone) that enhance extrasynaptic tonic inhibition and neurogenesis effectively control GWI chemical agent-induced neuronal damage and thereby completely mitigate neurological morbidity. Ganaxolone and related neurosteroids promote tonic inhibition, mediated by extrasynaptic receptors that play a critical role in controlling anxiety, memory, and hyperexcitability disorders. Cholinergic hyperactivation cause a huge decrease in synaptic GABA-ARs, with minimal change in extrasynaptic ?GABA-ARs (targets for neurosteroids). Neurosteroids also enhance neurogenesis, which is essential for recovery from brain injury. These concepts, as validated earlier in the CounterACT program, suggest the viability of tonic inhibition therapy for GWI. Broad-spectrum neuroprotection, safety profile, lack of tolerance, and ready availability make ganaxolone a practical drug for GWI. We will test this hypothesis by addressing three specific aims using young rats.