Treating Gulf War Illness via Modulation of Leukotriene Signaling
Abstract
Nearly 40% of military personnel who served in the first Gulf War have Gulf War Illness (GWI). The enduring nervous system-related health issues include learning difficulties, reduced ability to make new memories or retrieve recently formed memories, depression, anxiety, sleep problems, and chronic pain. Many potential causes have been suggested for GWI, based on epidemiological and animal model studies. A report by the Research Advisory Committee on GWI indicated that the various symptoms displayed by a significant percentage of PGW-1 Veterans were owed to the exposure to a mixture of malevolent chemicals during the war. The substances include pyridostigmine bromide (PB) and pesticides such as DEET and permethrin (PM) during the war. PB tablets were given to Service personnel as a prophylactic measure against a possible nerve gas attack by the enemy. Copious amount of pesticides such as DEET and PM were used on the skin and uniforms to combat insects and rodents during the war. Exposure to a chemical weapon (e.g., sarin) may also be the cause of GWI in some Veterans who were posted close to the chemical weapon depot demolitions. Nevertheless, it is widely believed that the neurological symptoms in a significant fraction of Gulf War Veterans are a consequence of an interaction of chemicals PB, DEET, and PM or interaction 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 moderate stress for 4 weeks causes enduring dysfunction of the hippocampus, a critical region in the brain facilitating learning, memory formation, and the maintenance of mood. Dysfunction of this region in a rat model of GWI is typified by learning difficulties, inability to make new memories or recall recently formed memories, and increased anxiety- and depressive-like behavior. Remarkably, these functional deficits were seen in parallel to chronic inflammation, reduced generation of new neurons, higher levels of cellular stress and mitochondrial dysfunction in the hippocampus, and elevated levels of proinflammatory compounds in the circulating blood. The various adverse alterations in the hippocampus and increased concentration of proinflammatory compounds in the circulating blood can interfere with learning, memory, and mood function either directly or indirectly by reducing neurogenesis in the hippocampus. Hence, drugs that can mediate robust anti-inflammatory activity as well as promote neurogenesis in the hippocampus might be highly beneficial for improving brain function 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 robust anti-inflammatory and neurogenesis-promoting activity in animal models of aging and neurodegenerative diseases. Montelukast appears promising for treating GWI because hippocampal alterations observed in animal models of aging have multiple similarities with animal models of GWI. A previous study has demonstrated that 6 weeks’ treatment of aged rats with Montelukast reduced inflammation and increased neurogenesis in the hippocampus along with reversal of learning and memory impairments. A clinical trial using Montelukast is also in progress for improving function in patients with Alzheimer’s disease. Montelukast inhibits leukotriene receptor signaling that mediates inflammation in the brain. Our studies in a rat model of GWI have demonstrated that leukotriene signaling is indeed enhanced in the brain of GWI rats. Furthermore, our preliminary results in a rat model suggest that Montelukast is a promising drug for improving brain function in GWI. These results support the idea that modulation of leukotriene signaling pathway through Montelukast would overcome the dysfunctional effects of GWI on the brain thr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910548
Entities
People
- Ashok Shetty
Organizations
- Texas A&M Health Science Center
- United States Army