Neuroinflammation-Related Phosphoprotein Signaling Pathways as Potential Therapeutic Targets for GWI Using an Established Animal Model
Abstract
It is estimated that approximately 200,000 of the over 700,000 Soldiers deployed to the 1991 Persian Gulf War returned home with a myriad of behavioral symptoms that only recently have been defined as Gulf War Illness (GWI). These symptoms mimic the feelings you have when you are sick and include fatigue, joint pain, nausea, and cognitive and memory deficits. Most people experience sickness behavior for a short period of time when exposed to a pathogen and promptly return to normal when the infection clears. GWI sufferers, however, report long bouts of more severe sickness behavior. Sickness behavior largely is associated with what can be described as a mild brain inflammation, i.e., an accumulation of inflammation molecules in the brain. These ?neuroinflammation? signals normally subside, but they appear to be present at higher and longer lasting levels in Veterans suffering from GWI. Because we cannot obtain brain inflammation data from living GW Veterans, we are using an animal model we have developed to study exposures and conditions similar to those Soldiers were experiencing in the Persian Gulf Theater. This approach allows us to understand GWI-related effects in brain, findings essential to understanding how GWI develops and how we can treat ill GW Veterans to alleviate their sickness symptoms that are still present over 25 years after the war. In our past CDMRP-funded research, we determined that GWI-relevant exposures and conditions (nerve agents, pesticides, and physiological stress) produce recurring brain inflammation in mice and rats, findings that may mimic what is happening in ill Veterans to cause their symptoms. Through CDMRP funding, we have been looking at the cell types in brain that likely are most responsible for causing the elaboration of molecules that cause chronic sickness behavior. By honing in on the cells responsible for making inflammation signals in the brain, we can more fully understand what types of exposures/conditions activate these cells and likely contribute to the symptoms of GWI. Then we can identify drugs that inhibit the activation of these cells by interfering with specific signaling processes in these cells. We are preferentially selecting drugs that have already been approved by the Food and Drug Administration so that these potential treatments can be rapidly administered to the ill Veterans. It is important to note that we do not know what causes GWI. One compelling notion has been that the neurotransmitter acetylcholine is involved. This makes sense because nerve agents and some pesticides are a type of compound known as organophosphates, and they bind irreversibly to the enzyme that metabolizes acetylcholine and keeps the action of this transmitter set to the ?on? position. Nevertheless, unlike our findings that GWI-relevant organophosphates result in brain inflammation, such organophosphate compounds are known to have anti-inflammatory effects via the actions of acetylcholine. This observation, and the fact that reversible inhibitors of acetylcholine metabolism don?t result in brain inflammation, make it unlikely that acetylcholine has a direct causative role in GWI. So what are the potential effects of organophosphates that relate to GWI? Organophosphates can bind to many, many molecules in the brain, and it is possible that key signaling pathways are affected by these yet-to-be-defined actions that result in symptoms we know as GWI. Therefore, our plan is to evaluate numerous brain signaling pathways potentially affected by ?organophosphorylation? and to identify new organophosphorylated targets using our mouse model of GWI. To achieve these goals, we will collaborate with colleagues at West Virginia University (selective phosphoprotein analysis), the Rochester General Hospital (computational biology), and SUNY at Buffalo (for novel target ID). We will take the information gained from analyses of the affected pathways and targets and subject the data
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910036XX0
Entities
People
- Jonathan W Boyd
Organizations
- United States Army
- West Virginia University