Gulf War illness (GWI), seen in nearly 30% of the 700,000 Persian Gulf War 1 (PGW-1) Veterans, is typified by multiple chronic health problems, which also includes brain-related impairments. The most noticeable brain impairments include cognitive problems, inability to make new memories, and depression. Multiple possible causes have been proposed for this illness. A comprehensive report by the Veterans Affairs Research Advisory Committee (VA-RAC) on GWI suggests that the symptoms displayed by a significant fraction of PGW-1 Veterans are most likely owed to an exposure to chemicals such as pyridostigmine bromide (PB) and pesticides such as DEET and permethrin (PM) during the war. These exposures were believed to have befallen due to the following situations. First, to decrease the harmful effects of a likely nerve gas attack during the war, the troops were given pyridostigmine bromide (PB) as a prophylactic treatment. Second, pesticides such as DEET and PM were widely used by troops on skin and uniforms to combat insects and rodents in the region. Causes of GWI in some Veterans likely also include exposure to chemical weapons (especially for those Veterans who were stationed near the chemical weapon depot demolitions). Thus, it is widely believed that the neurological symptoms in a vast majority of Gulf War Veterans are owed to a synergistic interaction of chemicals PB, DEET, and PM or interaction of one or more of these chemicals with war-related stress. Indeed, studies performed in our laboratory using a rat model showed that combined exposure to low doses of chemicals PB, DEET, and PM with or without mild stress for 4 weeks causes considerable dysfunction of the hippocampus, a region of the brain important for maintenance of normal memory and mood function. These include cognitive impairments, reduced ability for making new memories, and increased depressive-like behavior. Importantly, these changes were associated with increased oxidative stress, chronic low-level inflammation, and greatly declined neurogenesis (daily generation of new neurons) in the hippocampus. Because daily addition of new neurons to the hippocampus circuitry is an important process that contributes towards formation of new memories and maintenance of normal mood function, it is likely that greatly reduced hippocampal neurogenesis at least partly underlies the memory and mood impairments observed in this GWI model. Because both oxidative stress and inflammation can adversely affect cognitive, memory, and mood function either directly or indirectly through suppression of new neuron production (neurogenesis) in the hippocampus, it is likely that increased oxidative stress and chronic low-level inflammation are among the major causes underlying memory and mood impairments in GWI.

Thus, strategies that are capable of easing increased oxidative stress and chronic inflammation seem beneficial for enhancing hippocampal neurogenesis as well as cognitive, memory, and mood function in GWI. In this project, using an animal model of GWI, we propose to examine the efficacy of oral administration of curcumin (CUR) encapsulated biodegradable nanosystems (nCUR) for alleviating cognitive, memory, and mood dysfunction. Curcumin is a principal curcuminoid of turmeric (an ingredient used in Indian curries), which has been shown to have robust antioxidant, anti-inflammatory, and neurogenic properties in a multitude of disease models. More importantly, our recent studies show that administration of CUR greatly improves memory and mood function in a rat model of GWI with suppression of oxidative stress and inflammation and improved neurogenesis. Yet, CUR is yet to be approved as a therapeutic agent, due to its poor bioavailability in humans following oral administration. Therefore, in this project, we will rigorously examine the efficacy of nCUR for reversing memory and mood dysfunction and hippocampus oxidative stress and inflammation in rats afflicted with GWI-like symptoms. Based on our preliminary studies, nCUR has much greater bioavailability than CUR in rodents and hence administration of lower doses is likely to provide beneficial effects. Overall, the studies planned in this project are highly relevant towards developing a therapy for cognitive, memory, and mood impairments seen in PGW-1 Veterans.