Abstract: Veterans from the 1990-1991 Persian Gulf War (GW) are af?icted with Gulf War Illness (GWI) which is characterized by a constellation of unexplainable symptoms that include chronic pain, memory impairment and fatigue. Consequently, veterans with GWI have limited function and activities of daily, resulting in loss of productive years. Research studies provide compelling evidence that GWI may have been caused by exposure to chemicals, such as an anti-nerve agent pyridostigmine bromide (PB) and different types of pesticides (GW agents). In particular, the types of pesticides to which GW veterans were exposed are also those implicated in chronic neurodegenerative conditions associated with aging, such as Alzheimer' disease (AD) and Parkinson's disease (PD). A concern also raised by the Institute of Medicine (IOM) in their recent reports. Imaging studies show that the brain structures involved in processing and storing memory and brain pathways involved in controlling pain and fatigue are altered in GW veterans with GWI. Many of these brain structures (i.e. the hippocampus) are also affected in neurodegenerative illness. Over the last two decades, important clinical discoveries have been made which show that immune/in?ammatory and metabolic disturbances are contributors to the pathology of GWI. The Roskamp Institute (RI) scientists have been at the forefront of research aimed at identifying therapies for treating the central nervous system (CNS) symptoms associated with GWI. Previously, RI scientists developed a novel mouse model of GWI using GW agents (pyridostigmine bromide [PB] and pesticides) which exhibits neurobehavioral de?cits that are similar to symptoms reported in veterans with GWI. At chronic post- exposure time-points, GW agent exposed mice had astroglia and microglia activation in the brain, suggesting a presence of neuroin?ammation. Biochemical investigations show that GW agent exposed mice had abnormal phospholipid (PL) pro?les for species that contained ether linkages and omega-3 and omega-6 polyunsaturated fatty acids (PUFA). In this well-characterized GWI mouse model, there were also dramatic decreases in cardiolipins (CL) and acylcarnitines, lipids that are speci?c to mitochondrial function. We also observed changes in omega-3 and omega-6 PUFA, mitochondrial CL and acylcarnitines and very long-chain fatty acid (VLCFA) and branched chain fatty acid (BCFA) that are speci?c to peroxisomal function in the blood samples from veterans with GWI compared to GW era controls. Since these lipids are speci?c to immune/ in?ammation and mitochondrial and peroxisomal functions, our ?ndings suggest their involvement in GWI pathogenesis. Many of these lipids are those which contribute to oxidative stress and in?ammation associated with neurodegenerative illnesses. We therefore hypothesized that targeting omega-3 and omega-6 PUFA and mitochondrial and peroxisomal lipid metabolism may be useful in developing therapies which target in?ammation and metabolic disturbances associated with GWI. Targeting these lipids may also prevent GW veterans from developing neurodegeneration later in life. In this proposal, we will test novel natural compounds which target the above mentioned lipids in order to determine if these compounds can ameliorate cognitive dysfunction and astroglia and microglia activation in the brains of GW agent exposed mice. These studies will facilitate development of innovative intervention strategies which can be rapidly translated into clinical use for maximizing their bene?t in treating ill GW veterans who have been suffering from this condition for 25 years.