Gulf War Agent Exposure Causes Dose‐Dependent Impairment of Memory Formation and Exercise Intolerance in a Mouse Model of Gulf War Illness

• Published in: The FASEB journal 2021-05, Vol.35 (S1), p.n/a, Article fasebj.2021.35.S1.05389
• Main Authors: Kozlova, Elena, Carabelli, Bruno, Bishay, Anthony, Denys, Maximillian, Curras‐Collazo, Margarita
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2021.35.S1.05389

Gulf War Illness (GWI) is a chronic multi‐symptom condition that still affects a third of veterans who served in the 1991 Persian Gulf War (GW). Latently‐emerging and persistent symptoms fall into 5 general domains: neurological/cognition/mood, muscle/joint pain, respiratory, gastrointestinal disturbances and especially chronic fatigue. In particular, veterans exhibit CNS deficits in the neuropsychological domains of visuospatial abilities, attention/executive functioning, and learning/memory. GWI remains untreated due its poorly understood etiology and pathophysiology. It is suggested that GWI is a result of continuous exposure of military personnel to GW agents (pyridostigmine bromide, (PB), permethrin (PER), diethyltoluamide (DEET) and deployment/combat stress. To further investigate the cognitive manifestations of GWI pathophysiology, we studied the effects of chronic GW agent exposure in adult C57Bl/6N males utilizing a repeated measures design. The dosing paradigm consisted of 5 d/week for 28d of exposure to two doses of PB (6.5 mg/kg/d, 2x/d and 8.7 mg/kg/d, 1x/d; po), PER (1.3 mg/kg/d; top) in 70% ETOH, DEET (1650 mg/kg/d in DMSO) and stress 5 min/d (n=5–7/group). Two controls were included: sham (saline po, 70% ETOH and DMSO top) and sham/stress. Behavioral endpoints were measured at different timepoints post treatment (PT) up to PT160d. The 8.7 mg/kg/d dose was more effective in modeling cognitive deficits on the passive avoidance test since this group failed to avoid the aversive dark chamber at the 24h, and 7d and/or 3d retention timepoints at PT70. A repeat test at PT120 indicated that the 8.7 and sham/stress (P