New approaches for the Treatment of Neuroinflammatory and Behavioral Consequences of Exposure to Gulf War Illness Chemicals
Abstract
While therapeutic advances have been made to alleviate some of the acute symptoms of Gulf War Illness (GWI), the search for effective therapies for the chronic neurological symptoms associated with GWI continues. This is a critical problem in GWI, and the GWIRP has challenged the scientific community to provide research insights geared towards the development of novel therapies for GWI. Therefore, in our proposed research, we focus on a drug therapy that combines two already approved pharmacological agents that we hypothesize will reduce symptoms associated with injury in the central nervous system (CNS) from exposure to Gulf War agents. Using a rodent model of repeated exposure to an organophosphate (diisopropyl fluorophosphate; DFP) that is known to induce GWI in rodents, we and other investigators have demonstrated that the CNS undergoes changes that are consistent with a state of chronic inflammation that correlate with neurological morbidities. Other investigators have demonstrated that when rodents are pretreated with an antibiotic agent that inhibits the ability of microglia, the main immune cell of the CNS, from producing signals that lead to inflammation, CNS symptoms from DFP exposure are reduced. While inflammatory responses associated with microglia are essential for starting the repair process in an injured CNS, these data suggest that when exposed to DFP, microglia remain in a state where they continually release signals that maintain chronic inflammation in the CNS. While in this state, communication between microglia and the neurons within the CNS becomes confused, leading to additional injury, lack of repair, and the CNS symptoms of GWI, including anxiety, depression, other mood disorders, and cognitive dysfunction. This “altered neuroimmune crosstalk” is, at its core, the disruption of calcium communication between microglia and neurons that starts when neurons are injured by Gulf War agents. Current treatments for neuroinflammation are geared towards using anti-inflammatory agents alone. However, this approach ignores the “repair” aspect, thereby preventing the brain from moving beyond a chronic neuroinflammatory state and in constant need of anti-inflammatory agents. We have taken a completely new approach to treating GWI neuroinflammation that breaks the cycle of persistent inflammation within the brain and alleviates chronic depression and memory deficits in GWI rats. Our approach to restoring healthy neuroimmune crosstalk in GWI is the combination of two pharmacological agents. The combination pharmacotherapy includes a nonsteroidal anti-inflammatory drug (NSAID) and a drug that mimics prostaglandins, a hormone in the body associated with inflammation and calcium signaling. Naproxen, the NSAID we propose to use, blocks enzymes that produce prostaglandins, thereby blocking prostaglandins from increasing calcium through one of its four pathways. Misoprostol is a prostaglandin mimic that ignores the pathway that increases calcium, acting through the beneficial pathways alone. By redirecting prostaglandin signaling, rather than just by shutting it off entirely, we maintain that this will “re-educate” microglia to return to a protective state that will reduce inflammation and the chronic CNS symptoms of GWI. Therefore, we will restore healthy neuroimmune crosstalk by redirecting the calcium communication disrupted from injury of neurons by Gulf War agents. Clinically, we can move into patient populations within only a few years. While both naproxen and misoprostol are Food and Drug Administration (FDA)-approved and their individual benefits and risks have been studied, we need to ensure that the combination pharmacotherapy does not cause any unanticipated risks. In addition, it will be necessary to verify that the dose combination effective in our rodent model is also effective in a clinical setting. However, given that misoprostol is often taken in combination with NSAIDS to reduce
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910332
Entities
People
- Jamie Dewitt
Organizations
- East Carolina University
- United States Army