Browsing by Author "Shetty, Ashok"

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Melatonin for Reversing Brain Dysfunction in Gulf War Illness
Molecular And Cellular Medicine; TAMHSC; https://hdl.handle.net/20.500.14641/473; DOD-Army-Medical Research and Materiel Command
Multiple persisting health issues including brain dysfunction exemplify Gulf War Illness (GWI), which afflicts 25%-32% of the 700,000 Persian Gulf War 1 (PGW-1) Veterans. The most conspicuous brain-related impairments comprise learning difficulties, inability to make new memories or recall recent memories, depression, and sleep problems. A multitude of potential causes have been suggested for this ailment. A thorough report by the Department of Veterans Affairs Research Advisory Committee on GWI implied that the symptoms exhibited by a major percentage of PGW-1 Veterans are likely due to exposures to a mixture of chemicals that includes pyridostigmine bromide (PB) and pesticides such as DEET and permethrin (PM) during the war. These exposures were thought to have happened because of the following circumstances. The drug PB was given to Service personnel as a prophylactic treatment against possible nerve gas attack by the enemy. The pesticides such as DEET and PM were widely used by troops on skin and uniforms to combat insects and rodents in the desert. An exposure to chemical weapons is likely also the cause of GWI in some Veterans particularly those who were posted close to the chemical weapon depot demolitions. Nonetheless, it is widely believed that the neurological symptoms in a significant fraction of Gulf War Veterans is owed to an interaction of chemicals PB, DEET, and PM or interaction of one or more of these chemicals with war-related stress. Indeed, experiments performed in our laboratory using a rat model demonstrated that combined exposure to low doses of chemicals PB, DEET, and PM with mild or moderate stress for 4 weeks causes persistent dysfunction in the hippocampus, a region of the brain vital for making new memories and maintaining normal mood function. Dysfunction of this region was typified by learning difficulties, inability to make new memories or recall recently formed memories and anxiety or depressive-like behavior. Interestingly, these alterations were allied with persistently higher levels of reactive oxygen species, mitochondrial abnormalities, chronic low-level inflammation and greatly waned production of new neurons in the hippocampus. Greatly reduced hippocampal neurogenesis at least partly underlies memory and mood impairments observed in this GWI model because regular addition of newly born neurons to the hippocampus circuitry is a vital process that aids in the formation of new memories and preservation of normal mood. Since both oxidative stress and inflammation can adversely influence memory and mood function either directly or indirectly through reducing neurogenesis in the hippocampus, it is likely that persistently augmented oxidative stress and chronic low-level inflammation are among the major reasons behind memory and mood dysfunction in GWI. From these perspectives, drugs that are proficient for easing increased oxidative stress and chronic inflammation appear useful for improving both hippocampal neurogenesis and memory and mood function in GWI. Using a well-established rat model of GWI, we offer to investigate the effectiveness of oral administration of low to moderate doses of melatonin (MEL; an over-the-counter dietary supplement having robust antioxidant, anti-inflammatory, and sleep promoting properties) for improving, learning, memory, and mood function. Earlier studies have shown that MEL is efficacious for: (i) providing protection against developing Alzheimer’s disease and Parkinson’s disease, (ii) reducing the size of infarct area in stroke, (iii) minimizing brain swelling and dysfunction after a head injury, and (iv) improving the lifespan. Furthermore, MEL intake can promote better sleep, which is important since sleep disturbances is one of the major brain-related issues in GWI. Our preliminary studies in a rat model support the idea that MEL treatment has potential to alleviate several brain-related impairments seen in GWI. Therefore, using a rat model of chronic GWI, we propose to rigorously test the usefulness of low to moderate doses of MEL for improving memory and mood function along with suppression of oxidative stress and inflammation in the hippocampus. Taken together, the proposed studies are extremely pertinent towards developing a treatment that improves cognition, memory, and mood function in PGW-1 Veterans.