Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

Abstract

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War Illness

“…Histopathological analyses of this PB+PER mouse model revealed an increase in astroglia activation in exposed mice (Abdullah et al, 2011;Zakirova et al, 2015), which is also observed in several other rodent models of GWI (Abdullah et al, 2012;Abdullah et al, 2011;Zakirova et al, 2015;Parihar et al, 2013;Ojo et al, 2014). In the brain, astroglia play a fundamental role in providing support to neurons by maintaining the extracellular environment and delivering nutrients to neurons that are acquired from the peripheral circulation.…”

“…GWI, identifying molecular changes in the brain necessitates the use of well-established animal models of GWI. We developed a GWI mouse model using combined exposure to PB and PER that exhibits anxiety and cognitive problems that are similar to the symptoms reported by veterans with GWI (White et al, 2016;Abdullah et al, 2011;Zakirova et al, 2015;Sullivan et al, 2003). Hence, this mouse model captures one of the key clinical features of GWI and is suitable for examining long-term changes that are relevant to the current clinical condition of veterans with GWI.…”

“…All animal experiments were approved by the Institutional Animal Care and Use Committee and performed as previously described (Abdullah et al, 2011;Zakirova et al, 2015). Male C57BL6 mice (3-months of age, weight 25 g ± 0.7 SD) were co-administered 0.7 mg/kg of PB and 200 mg/kg of PER in a single intraperitoneal injection volume of 50 μl in dimethyl sulfoxide (DMSO) or the same volume of DMSO alone (control) daily for 10 consecutive days (n = 10 for controls, n = 9 for GW agent exposed mice).…”

“…The doses of PB and PER are less than 1/5 and 1/2 of the known LD50 values in rodents, respectively (Chaney et al, 2002;Williamson et al, 1989). Given the paucity of information on doses and routes of PER exposure, we used 200 mg/kg of PER to mimic a high-level exposure that is similar to that used in mice by previous studies showing adverse behavioral or pathological outcomes (Abdullah et al, 2011;Zakirova et al, 2015;Dodd, & Klein 2009;Pittman et al, 2003). The cis/trans ratio of PER were based on the recommended by the World Health Organization (25% cis and 75% trans) (WHO 2003).…”

Phospholipid profiling of plasma from GW veterans and rodent models to identify potential biomarkers of Gulf War Illness

“…As reported above, the PB+PER mouse model and the PB+PER+DEET and stress rat model utilized in this study have been well characterized with respect to neurobehavioral features that are similar to chronic symptoms reported by GWI patients [9,10,41,44,47]. Samples from both rodent models were collected at 6 months post exposure.…”