Development and characterization of an aging rat model of sustained Gulf War Illness

Abstract

Gulf War Illness (GWI) afflicts ~30% of the US military personnel who served in the 1990‐91 Persian Gulf War. Prominent symptoms include cognitive deficits such as anxiety, memory impairment and fatigue. Currently, no treatments are available for GWI and the afflicted Veteran population has aged by an additional 30 years to an average age of mid‐50s. As per the expected effects of GWI plus aging, one would hypothesize that cognitive and muscle related symptoms would be further aggravated. With this goal in mind, we implemented an aging rodent model of GWI whereby young male rats. Animals were exposed to GWI chemicals/stress for 4 weeks or vehicles/no stress (controls) and allowed to age under normal conditions and feeding for an additional 15 months so as to replicate the current aging profile of Gulf War Veterans. Cohorts of 3 month old male Wistar control and GWI rats were implemented with an average initial body weight of ~260 g. Over a period of about 70 weeks, animals approximately doubled their body weight with no significant differences between both groups. Figure 1 reports on an average change in front limb strength of control rats over a period of 58 weeks. Limb strength is recorded in Newtons (N) and is normalized to animal weight (g). As can be observed, a clear trend for decreases in normalized front limb strength occurs over time. Figure 2, plots front limb strength recorded over a period of 58 weeks in control and GWI rats. As can be observed, a sustained difference is noted following a 4 week exposure to GWI chemicals (week 0‐4) that starts at week 8 and is sustained in a significant manner over a period of ~50 weeks. Thus, exposure to GWI chemicals/stress triggers a sustained long‐term phenotype that can be detected by measures of muscle strength. Studies were also implemented to assess changes in neurocognitive behavior as recorded at week 58. GWI animals demonstrate a greater level of anxiety as per significant differences noted in time spent in central vs. peripheral (wall) areas. Measures of short and long‐term memory were obtained using the object preference test. GWI rats exhibit a significant decrease in short‐term memory which was not evident in long‐term measurements. In summary, limited exposure of healthy young rats to GWI chemicals/stress triggers as in GWI patients, a sustained disease phenotype in muscle and neurocognitive measures that may be amenable to treatment with agents that stimulate mitochondrial bioenergetics and/or reverse muscle atrophy. This premise is currently being tested in this cohort of aging control and GWI rats using the cacao flavanol epicatechin.