Behavioral profiling of aged glutathione-deficient mice exposed to an oxidative stressor

Purpose Aging is associated with a decrease in brain function and vitality, along with an increased risk to stressors. Oxidative stress is a mechanism associated with aging, in which antioxidant defenses are overcome by the production of reactive oxygen species, leading to molecular damage and decreased cellular efficiency. Glutathione is a major antioxidant and indicator of cellular redox status, however its role in resilience remains unclear. To determine its involvement, we used the oxidative stressor paraquat (N,N′-dimethyl-4,4′-bipyridinium dichloride; PQ), a widely used herbicide that is highly toxic to animals and humans, in a mouse model of glutathione deficiency. The purpose of this study was to determine if paraquat-induced oxidative stress would exacerbate age-associated functional impairments in glutathione deficient mice. Methods Groups of old (18 months) male and female gclm+/+ and gclm-/- mice were assigned to a control group (saline) or a paraquat group (10 mg/kg; once via i.p.). One week following the injection, animals underwent behavioral testing of motor, affective and cognitive function (bridge walking, wire suspension, coordinated running, locomotor activity, elevated zero maze, fear conditioning, and active avoidance). Results Gclm-/- exhibited less anxious behavior than the gclm+/+, and PQ had no effect on that measure. Gclm-/- were more active than the gclm+/+, and PQ reduced that activity especially in females. PQ treatment seemed to improve cognitive flexibility, and improved associative learning in males only. PQ improved balance and strength of the gclm-/- in females, but worsened the strength in gclm+/+ males. Conclusion Overall, this study indicates that PQ did not exacerbate any phenotype associated with glutathione deficiency, and in some instances, it made the mice better. These outcomes do not support an involvement of glutathione in resiliency, however its life-long deficiency may have led to upregulation of other protective mechanisms making the mice stronger in adverse situations.