Role of Activated Microglia in Brain Dysfunction in a Model of Chronic GWI
Abstract
Gulf War Illness (GWI) is a multi-symptom disease affecting ~40% (~200,000 out of 700,000) Veterans who served in the first Gulf War. The symptoms related to the brain include cognitive impairment, problems with making and recalling the memory, concentration issues, and sleep disturbances. Epidemiological and animal studies implied that exposure to GWI-related chemicals such as pyridostigmine bromide (PB, a prophylactic drug against nerve gas) and pesticides (e.g., permethrin PER) led to neurological problems in a significant percentage of GW Veterans. Indeed, mice exposed to higher doses of PB and PER for 10 days display a phenotype that mimics the chronic symptoms of GWI. The most conspicuous symptoms include unremitting cognitive and mood impairments associated with chronic neuroinflammation typified by activated microglia and reactive astrocytes. Experimental models of chronic GWI have suggested that the predominance of activated microglia is one of the factors contributing to brain fog in GWI. Studies in several neurodegenerative disease models have shown that removing most of the activated microglia by inhibiting one of the receptors that maintain their survival can effectively replace the microglial compartment with new healthy noninflammatory microglia. Furthermore, the repopulated microglia has been shown to reduce cognitive problems along with diminished neuroinflammation. Chronic neuroinflammation and cognitive and mood impairments are also seen in chronic GWI. Therefore, we postulate that replacing inflammatory microglia with noninflammatory microglia would ease chronic neuroinflammation, and facilitate better cognitive and mood function in chronic GWI. We propose to test the effects of removing activated microglia on cognitive function in a mouse model of chronic GWI, using a drug (PLX5622) that inhibits one of the receptors maintaining microglia survival. Once the activated microglia are removed, new noninflammatory microglia repopulate the brain, which allows testing whether replacing activated microglia with noninflammatory microglia would improve cognitive and mood function in GWI. Studies in several neurodegenerative disease models have shown that the repopulated noninflammatory microglia alleviate cognitive dysfunction with diminished neuroinflammation, but such effects have not been tested in the GWI model. Since neuroinflammation with activated microglia is also seen in chronic GWI, we anticipate that the replacement of pathological microglia by healthy microglia would reduce the overall inflammation and improve brain function in GWI. In summary, the proposed study will uncover whether replacement of proinflammatory microglia by noninflammatory microglia would improve cognitive and mood function in a mouse model of chronic GWI and whether such improvements are associated with inhibition of inflammatory pathways perpetuating brain dysfunction in GWI. If successful, the results would provide a new avenue for treating chronic neuroinflammation and cognitive and mood problems in veterans afflicted with GWI using Food and Drug Administration (FDA)-approved drugs such as fingolimod that modulates the conversion of pathological microglia and into healthy microglia. The proposed studies have the promise to improve the quality of life of Veterans with GWI in the long term.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210749
Entities
People
- Maheedhar Kodali
Organizations
- Texas A&M Health Science Center
- United States Army