Military Veterans of the 1990-1991 Persian Gulf War have a higher incidence of chronic multi-symptom health problems compared to non-deployed military personnel or those deployed in other regions. It has been over two decades since the conflict; yet to this day, most Veterans with Gulf War Illness (GWI) continue to suffer from debilitating, medically undiagnosed chronic symptoms that characterize the multifaceted, complex nature of the disease. Thus, there remains an urgent need to develop effective drug therapies to treat GWI.
While the causes of these symptoms are not fully understood, there is ample evidence that suggests that the chemicals pyridostigmine bromide (PB) and permethrin (PER) are principal causative agents for GWI. PB, an acetylcholinesterase inhibitor, was given to Soldiers as a prophylactic treatment against nerve gas exposure, while PER is a commonly employed pesticide used to protect against pest-borne illnesses. The mechanism(s) by which these compounds may have triggered the illness, as well as the current persistence of their effects many years after the original exposure, remain unknown. Despite this, one detail is clear: the population of Veterans with GWI (roughly 1 in 4 of the 697,000 Veterans) has been suffering with this illness for decades. Therefore, attempting to target the original, primary cause of their condition with therapeutic interventions is likely futile. However, identification of biological pathways associated with long-term symptoms will likely prove crucial to developing novel, effective therapies for this disease.
We have developed a mouse model of exposure to PB and PER in which mice are exposed for just 10 days as young adults in order to mimic the typical age of our Veterans at the time of their exposure. We have discovered that, over time, these mice develop memory impairment and pathological modifications in the brain that correlate with changes at the molecular level, enabling us to identify several potential targets for therapeutic intervention in GWI. Such changes include excessive activation of brain cells known as astrocytes, which are responsible for providing biochemical support to other cells (i.e., nutrient delivery, maintaining ion balance, and play important roles in inflammatory responses and repair mechanisms after brain injury or insult). Another important therapeutic target that we have identified is associated with oxidative damage, specifically to the mitochondria, the main organelles responsible for cellular energy. Our entire repertoire of selected targets is aimed at mitigating neuroinflammation and repairing perturbed “brain energetics,” or changes in brain metabolism, as well as memory and behavioral deficits in our exposed mice.
Previously, we have worked for many years to identify the molecular pathways and key molecules disrupted by the damaging exposure suffered by our GWI Veterans, and we are now at the stage of attempting to treat the chronic symptoms observed in our mouse model of GWI as a first step toward validating treatments for our patient population. We have selected five compounds, all of which have previously been used in humans, which we plan to administer to our mice at a time point that simulates treatment of patients already demonstrating GWI: the late-stage symptoms in humans (~5 months after exposure to the GW agents). This study will be conducted over 3 years and will be divided into three phases.
In the first aim, we will validate the long-term effects of an anti-inflammatory compound with which we have previously shown positive effects in our mouse model with short-term treatment. In Aim 2, we will test two compounds that modulate energy production and two that oppose the production of reactive oxygen species also known as “free radicals.” We will evaluate the effects of the different treatments using behavioral testing, neuropathological analyses, and molecular level analyses in our mouse model. Finally, in the third aim we will implement a combinatorial, therapeutic approach, by combining the anti-inflammatory treatment with the best candidate from the compounds targeting energy production or free radicals, to see if the combination will be more effective than the individual drug therapy. In all cases, we will determine whether our treatments will successfully mitigate the deleterious consequences of GW agent exposure in our mice. Our team is highly skilled and experienced in advancing potential therapeutics through animal testing and into clinical trials in human patient populations, and we are therefore confident that this project will result in a major step toward more effective treatments for GWI.