Glutamate Receptor and Kynurenine Pathway Functioning in the Pathobiology of Gulf War Illness
Abstract
Scientific Objective and Rationale: Gulf War Illness (GWI) affects about one-third of all 1990-1991 Gulf War Veterans. A large body of research now links GWI to neurotoxicant exposures encountered by military personnel during the Gulf War. Ongoing research in Gulf War Veterans and in animal models points towards long-term changes in the brain and immune processes that gave rise to a persistent inflammatory state in Veterans with GWI. These changes are most prominent in the brain and nervous system, where they produce inflammatory compounds that can produce a cluster of symptoms known as ?sickness response,? a profile similar to GWI and characterized by cognitive impairment, debilitating fatigue, widespread pain, and other persistent symptoms. Sustained immune system activation and oxidative stress can alter specific pathways in the brain that are driven by a family of compounds known as kynurenines. In recent years, much has been learned about the two major ways these compounds can be affected in the brain and how they act to perpetuate an ongoing cycle of inflammation that can produce GWI symptoms. One pathway involves stimulation of microglia, the immune cells of the brain that normally support functioning of brain cells. Activation of this pathway increases production of the kynurenine quinolinic acid. Quinolinic acid stimulates the immune system and oxidative stress in the brain and increases activation of cells that produce glutamate. Glutamate is the primary stimulating neurotransmitter, or nerve cell messenger, and can damage brain cells when activity is too high. The other major pathway involves stimulation of astrocytes, another type of brain cell that supports brain functioning. Activation of this pathway produces a different compound, kynurenic acid. Kynurenic acid can be protective by suppressing inflammation and oxidative stress in the brain and can reduce the production of glutamate. However, excess levels of kynurenic acid can result in problems with attention and thinking. Studies in animals and in patients with illnesses resembling GWI revealed these symptoms can be linked to activated microglia (suggesting higher quinolinic acid) or astrocytes (suggesting higher kynurenic acid). Studies have also shown that blocking the effects of excess glutamate can reduce symptoms associated with GWI, most prominently widespread pain. Our proposed study will provide a detailed evaluation of these processes in Gulf War Veterans in order to determine the pathways and specific compounds that are dysregulated and underlie symptoms of GWI. We propose that high quinolinic acid or kynurenic acid, and high glutamate cell activity, link immune system activation and oxidative stress to GWI symptoms. Ultimate Application: The study will provide identification of specific pathways and compounds that are dysregulated in GWI and can be targeted for treatment. Treatments that modulate the specific pathways studied in this proposal are already available and are currently used or being tested in humans with other illnesses.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710488
Entities
People
- Marijn Lijffijt
Organizations
- Baylor College of Medicine
- United States Army