Role for Calcium-BDNF Dysregulation in Gulf War Illness Neurological Symptoms and Its Alleviation by Carvedilol Therapy
Abstract
Overarching Challenges: In agreement with the Gulf War Illness Research Program (GWIRP) mission and the recommendations from The Gulf War Illness Landscape document, we respond with an Idea Award Application (discovery phase) by designing high-impact research that aims to directly advance GWIRP mission and will provide a better understanding of the mechanisms of GWI and develop treatment strategies for GWI. Rationale: Approximately one-third of the First Gulf War Veterans continue to suffer from Gulf War Illness (GWI) exhibiting debilitating symptoms including fatigue, pain, mood disorders, concentration deficits, and memory problems that dramatically affects their well-being and productivity with devastating impacts on quality of their lives, families, and caregivers. With strong support from the GWIRP, we developed a preclinical model of GWI-like neurological signs in rats following repeated, low-dose exposure to an organophosphate and nerve agent sarin analog diisopropyl fluorophosphate (DFP), a class of chemical compound that was present in the GW theatre and has been implicated for GWI. Using this model, we identified chronic elevations in brain calcium levels and also significant reductions in the levels of Brain Derived Neurotrophic Factor (BDNF). These are important findings since alterations in calcium levels can lead to abnormal cellular signaling and activation of degradative pathways similar to those seen in other neurological conditions such as Parkinson’s disease, Alzheimer’s disease, and traumatic brain injury. Similarly, reductions in BDNF levels have also been found in depression and memory disorders, many of the same disease conditions that share symptomatology with GWI. Next, we attempted to modify calcium and BDNF levels in DFP rats with Food and Drug Administration (FDA)-approved drugs namely levetiracetam and ketamine and observed that treatment with these agents significantly improved GWI signs in our preclinical rat model. These findings indicate that the calcium-BDNF signaling could be an important molecular target in GWI. Objective: It is therefore important to understand how these molecular changes are contributing to GWI persistence. The role of BDNF is to promote connections between neurons and this involves stimulation of neuronal projections called dendritic spines. Our previous research in conjunction with the preliminary studies included in this application showed that, in addition to BDNF reductions, DFP rats exhibited a significant reduction in dendritic spines. Spines are neuronal structures that contain signaling machinery and are also the sites for neuronal integration. A reduction in spine density, as seen in our GWI model, is also reported in Alzheimer’s disease, depression, and other mood disorders. Interestingly, we also saw alterations in specific spine types in the DFP rats. A reduction in the mushroom (M-type) spines was noted. These spines are implicated in memory processes. Thus, reductions in BDNF and alterations in spine density and spine types could partially explain the molecular basis of GWI. We therefore hypothesize that calcium/ BDNF dysregulations drive the abnormal synaptic plasticity, which underlies the development and persistence of GWI symptoms. Applicability: As we previously reported, our attempts to independently target calcium signaling and boost BDNF levels showed improvements in GWI rat behavior. During the course of these investigations, we came across another interesting compound – carvedilol. This drug is FDA approved for the treatment of hypertension. Published studies show that carvedilol is neuroprotective and decreases oxidative stress. It is also reported that carvedilol decreases elevated calcium levels by limiting ryanodine receptor open-time and is also shown to increase BDNF levels. These are the same mechanisms that we have found to be altered in our GWI model. Thus, carvedilol could potentially be a single agent therapy that could ta
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210993
Entities
People
- Laxmikant S. Deshpande
Organizations
- United States Army
- Virginia Commonwealth University