Melatonin for Reversing Brain Dysfunction in Gulf War Illness
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Background: Gulf War Illness (GWI), a chronic multi-system sickness affecting 25%-32% of Veterans who served in the Persian Gulf War 1 (PGW-1), is typified by fatigue, musculoskeletal pain, respiratory and gastrointestinal complications, and multiple central nervous system (CNS) deficiencies. Impaired cognition, memory, mood, concentration, and sleep are among the major CNS issues. While the precise cause of GWI is unknown, numerous causes have been proposed based on various exposures believed to have occurred to Service personnel during the war. Among these, the idea that GWI is a consequence of exposures to pyridostigmine bromide (PB) and pesticides such as permethrin (PM) and DEET during the war has received great interest. These exposures have occurred to a major fraction of Veterans because (i) Veterans who were posted in the battlefield areas have consumed pills of PB as a prophylactic measure to protect against nerve gas attacks by the enemy and (ii) copious amounts of pesticides and insect repellants were used around tents, uniforms, and skin as a measure to offset infectious diseases transmitted by insects/ticks in the desert. Thus, the chemical exposure hypothesis states that the CNS symptoms displayed by a major fraction of PGW-1 Veterans are due to interaction of PB with pesticides and/or war-related stress. This theory has been validated by the Research Advisory Committeeâ€™s report that the overall prevalence of GWI is greater in those who used higher amounts of pesticides than Veterans who had limited exposure to such agents during PGW-1. Coherent with this concept, studies in our laboratory using rat models have shown that a combined exposure to low doses of chemicals PB, PM, and DEET with mild or moderate stress for 4 weeks causes persistent dysfunction of the hippocampus, an area of the brain important for cognition, memory, and mood. The hippocampal dysfunction in this animal model is characterized by: (i) enduring learning, memory, and mood dysfunction; (ii) increased oxidative stress evidenced through higher malondialdehyde concentration and an enhanced expression of genes that typically respond to enlarged levels of reactive oxygen species (ROS) and mitochondrial dysfunction; (iii) chronic inflammation evinced by the presence of reactive astrocytes and activated microglia; and (iv) a greatly waned neurogenesis, a substrate believed to be involved in making new memories and maintaining normal mood. In addition, this model also exhibits chronic systemic inflammation. These findings gave the suggestion that increased oxidative stress, chronic inflammation, and declined neurogenesis in the hippocampus along with systemic inflammation are amid the major causes underlying cognitive, memory, and mood impairments in GWI. Thus, drugs capable of reducing oxidative stress and inflammation and enhancing neurogenesis in the hippocampus and/or dampening systemic inflammation may reverse cognitive, memory, and mood impairments in Veterans afflicted with GWI. We propose to test the efficacy of oral administration of melatonin (MEL; a hormone synthesized mainly by the pineal gland and having robust antioxidant and sleep-inducing properties) for easing cognitive, memory, and mood dysfunction in a rat model of GWI.Objectives and Hypothesis: We will examine whether oral administration of low to moderate doses of MEL improves cognitive, memory and mood function in rats displaying chronic GWI via suppression of oxidative stress and inflammation and/or modulating neurogenesis in the hippocampus.Specific Aims: In Specific Aim 1 (SA1), we will enumerate the effectiveness of oral administration of low and moderate doses of MEL (5 times/week for 8 weeks) for improving cognitive, memory and mood function when the treatment is commenced at an extended time point (6 months) after exposure to GWI-related chemicals and stress. The 6-month waiting period after exposure is equivalent to ~17 years survival period after exposure in humans. This extended waiting period is needed to simulate the chronic nature of ailment in GWI patients. The goal is to find the lowest dose of MEL that is beneficial for improving brain function in GWI and to assess the possible side effects of MEL when administered at higher doses on hippocampus structure and function. In Specific Aim 2 (SA2), we will investigate whether improved cognitive, memory, and mood functions in GWI rats receiving different doses of MEL are positively correlated with suppression of oxidative stress and inflammation and normalized neurogenesis in the hippocampus and/or modulation of systemic oxidative stress and inflammation. The goal is to find an optimal dose of MEL that not only suppresses oxidative stress and inflammation but also enhances hippocampal neurogenesis in association with improved cognition, memory, and mood.Study Design: We will first expose rats to GWI-related 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. Six months after the exposure, rats will be treated orally (5 times/week for 8 weeks) with one of the five doses of MEL (5, 10, 20, 40 or 80 mg/Kg/day, dissolved in water) or vehicle. Following the completion of this treatment regimen, we will analyze cognitive, memory, and mood function using a battery of behavioral tests (SA1 studies), followed by euthanasia and examination of hippocampal and cortical tissues for the extent of oxidative stress, inflammation, and neurogenesis (SA2 studies).Impact: This study proposes to investigate the efficacy of a dietary supplement having potent antioxidant and sleep-inducing properties for improving cognitive, memory, and mood function and hippocampal neurogenesis in a rat model of GWI. Thus, studies proposed in this project are highly relevant towards developing an apt therapy for cognitive, memory, and mood problems affecting Veterans of PGW-1.