Treating Gulf War Illness via Modulation of Leukotriene Signaling Grant uri icon


  • Background: Impairments linked to the brain function are among the chief health problems seen in Gulf War Illness (GWI). These are exemplified by cognitive and memory problems, depressive mood, and anxiety. Although the precise cause of GWI is unclear, epidemiological and animal model studies imply that GWI in majority of first Gulf War Veterans is a result of exposure to multiple chemicals such as the nerve gas prophylactic drug pyridostigmine bromide (PB) and pesticides during the war. Combined exposures to PB and pesticides believed to have occurred because: (i) Veterans stationed in the battlefield areas consumed PB pills daily during the war as a protection against a possible nerve gas attack and (ii) pesticides and insect repellants were employed liberally to offset infectious diseases transmitted by insects and ticks in the desert. The measures included pesticide sprays around tents and insect repellents on the skin and the uniform. The pesticides included the insecticide permethrin (PM) and the insect repellant DEET. Indeed, a report by the GWI Research Advisory Committee highlighted that the overall prevalence of GWI is higher in Veterans who used greater amounts of pesticides during the war. Moreover, studies in our laboratory have shown that combined exposure to low doses of chemicals PB (oral), PM (dermal), and DEET (dermal) with moderate stress for 4 weeks in rats causes chronic dysfunction of the hippocampus. The dysfunction is exemplified by impairments in cognition, memory, and mood, in association with multiple cellular and molecular changes in the hippocampus. These comprise chronic low-level inflammation with hypertrophied astrocytes and activated microglia, increased leukotriene signaling, elevated oxidative stress with activation of nuclear factor erythroid 2-related factor 2 (NRF-2, a master regulator of oxidative stress), and mitochondrial dysfunction. Also, new neuron production in the hippocampus showed a persistent decrease. Importantly, these changes in the hippocampus were linked with incessantly elevated levels of proinflammatory cytokines and oxidative stress markers in the circulating blood. Chronic inflammation, increased leukotriene levels, elevated oxidative stress, and mitochondrial dysfunction in the hippocampus and/or chronically elevated systemic inflammation can adversely affect cognitive, memory, and mood function either directly or indirectly through reduced neurogenesis. Hence, drugs that can mediate robust anti-inflammatory and antioxidant activity and promote neurogenesis might be beneficial for alleviating brain dysfunction in GWI. In this context, Montelukast, a Food and Drug Administration (FDA)-approved drug for the treatment of asthma, is one of the promising drug candidates that can be repurposed for treating GWI because of its proven anti-inflammatory effects (through inhibition of cysteinyl leukotriene signaling) and neurogenesis-promoting activity (via inhibition of GPR17 signaling) in animal models of aging and neurodegenerative diseases.Objectives and Hypothesis: We will test the efficacy of different doses of Montelukast for alleviating cognitive, memory, and mood dysfunction through suppression of brain and systemic inflammation and improved hippocampal neurogenesis in rats stricken with GWI-like symptoms. The therapeutic efficacy of the drug will also be tested at an extended time point after exposure to GWI-related chemicals and stress.Specific Aims: In Specific Aim 1 (SA1), we will measure the effects of different doses of Montelukast treatment for 8 weeks on cognitive and mood function, inflammation and oxidative stress in the brain, and hippocampal neurogenesis. Treatment will start 4 months after exposure to GWI-related chemicals and stress. The goal is to find an optimal dose of Montelukast that not only suppresses inflammation and oxidative stress, but also enhances neurogenesis in association with improved cognition, memory, and mood. In SA2, we will test whether an apt dose of Montelukast treatment for 12 weeks is efficient for alleviating cognitive, memory, and mood impairments in rats afflicted with chronic GWI, with treatment commencing 9 months after exposure. The goal is to test the ability of Montelukast to alleviate brain dysfunction seen in the chronic phase of GWI. Commencing treatment 9 months after exposure in rats is equivalent to starting treatment ~27 years after exposure in humans. The proposed waiting period is needed to simulate the scenario in patients currently suffering from GWI, as >27 years have passed since the first Gulf War.Study Design: We will first expose rats to GWI chemicals PB (2 mg/Kg, oral), DEET (60 mg/Kg, dermal), and PM (0.2 mg/Kg, dermal) and stress (15 minutes of restraint stress) for 28 days. In SA1 studies, 2 months after exposure, rats will be treated orally (5 times/week for 8 weeks) with one of the four doses of Montelukast (5, 10, 15, 20 mg/Kg/day) or vehicle. In SA2 studies, 9 months after exposure, rats will be treated orally (5 times/week for 12 weeks) with Montelukast or vehicle. The dose for this group will be chosen based on the results of the dose-response study performed in SA1. Following drug treatment, animals will be analyzed for cognitive, memory, and mood function using a battery of behavioral tests. Next, animals will be euthanized and brain tissues will be evaluated for inflammation, leukotriene levels, oxidative stress, and hippocampal neurogenesis using cellular, biochemical, and molecular biological methods. Systemic inflammation will also be evaluated using serum samples from animals.Impact: This study proposes repurposing of an FDA-approved drug for alleviating cognitive, memory, and mood dysfunction and neuroinflammation via modulation of leukotriene signaling and enhanced hippocampal neurogenesis, in rats afflicted with chronic GWI-like symptoms. Thus, studies proposed in this project are highly relevant to developing an apt drug therapy for cognitive and m

date/time interval

  • 2019 - 2022