Browsing by Department "Neuroscience & Experimental Therapeutics"

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Neurosteroid Therapy for Gulf War Illness
Neuroscience & Experimental Therapeutics; TAMU; https://hdl.handle.net/20.500.14641/531; U.S. Army Medical Research Acquisition Activity
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.
Vagus Nerve Stimulation as a Treatment Strategy for Gulf War Illness
Neuroscience & Experimental Therapeutics; TAMHSC; https://hdl.handle.net/20.500.14641/423; DOD-Army-Medical Research and Materiel Command
The objective for this proposal is to examine vagus nerve stimulation as a potential therapeutic strategy to treat Gulf War Illness (GWI). Our proposal aims to demonstrate proof of concept showing that vagus nerve stimulation (VNS) will reverse GWI-like symptomology in an established animal model of exposure compounds that Gulf War Veterans encountered in the theater. Successful completion of our proposed studies and positive results in one or more of our variables would be significant first step toward providing a basis for moving this treatment to the clinic. As the device is already Food and Drug Administration-approved and a transdermal device is under development, it is likely that should our results support our hypothesis, it would be highly feasible to rapidly translate this therapy to the clinic. In fact, VNS has already been successfully used off-label to treat debilitating headaches, migraines, and arthritis, the former two of which are also observed in many Gulf War Veterans. Thus, the likely contributions of this study in advancing the field of GWI research is that it may provide a foundation for the implementation of this safe, approved therapeutic intervention. VNS is currently approved to treat epilepsy and depression that have been resistant to pharmacological treatments. The vagus nerve is known to be fundamentally involved in regulation of the immune response in the periphery, the immune response in the brain and spinal cord (e.g., the neuroimmune response), and in regulating autonomic nervous system function. Because one or more of these systems is implicated in and/or observed to be dysfunctional in GWI, VNS might be directly applicable as a treatment strategy. In a wide range of clinical and experimental studies, stimulation of the vagus nerve has a demonstrated track-record of safety and efficacy in improving immune, neuroimmune, and autonomic outcomes. Of further interest to the GWI population is that research is currently underway to explore the potential usefulness of a non-invasive, transdermal VNS paradigm. Thus, further improvements to this technique may render it less invasive, which would further the appeal of this therapeutic strategy. Regardless of the method of stimulating the vagus nerve, the safety of VNS has been clearly demonstrated in over 700,000 patients. Therefore, this potential treatment offers the possibility of significant and relatively immediate benefits with minimal risks. We strongly believe that VNS treatment could be beneficial to GWI symptomology that could greatly enhance the lives of a large percentage of Gulf War Veterans.