Influence of exogenous oxidative stress on the resilience of aged glutathione-deficient mice

Influence of exogenous oxidative stress on the resilience of aged glutathione-deficient mice  Delaney L. Davis, J. Thomas Mock and Nathalie Sumien    Introduction  With age, individuals become less resilient against stressors, rendering them more susceptible to diseases and leading to exacerbated brain impairments. Aging also involves a shift in redox state that can be associated with the key molecule, glutathione. To determine the importance of glutathione in stress resilience, we sought to study the effect of an oxidative stressor (paraquat) in an animal model of chronic glutathione deficiency. Glutathione deficiency can be achieved by the genetic knockout of the modifier subunit of the enzyme, glutamate cysteine ligase (gclm). Our hypothesis was that chronic glutathione deficiency will render mice less resilient to the oxidative stress induced by paraquat and will cause further impairments in motor and cognitive function. Methods   Old (18 months) male and female gclm+/+ and gclm-/- mice received one to two intraperitoneal injections of 10 mg/kg of paraquat (PQ) or saline for one week. Four days following the last injection, animals underwent behavioral tests measuring affective, cognitive and motor function (locomotor activity, elevated zero maze, bridge walking, wire suspension, fear conditioning, rotorod, and active avoidance). After the completion of behavioral testing, brain regions, skeletal muscle, liver, heart, and kidney tissues were harvested and will be used to examine biochemical changes in oxidative damage and redox signaling. The data were analyzed using 2 or 3-way ANOVAs followed by pairwise comparisons. Results  Body weights in male and female mice dropped immediately after PQ injection, with the gclm-/-treatment group having a greater decrease in percentage of body weight than the gclm+/+. PQ injections appeared to decrease overall activity of both gclm+/+ and gclm -/-. PQ-treated mice seemed to spend less time in open arms, indicating increased anxiety levels. Overall, PQ-treated mice appeared to perform better on motor skills and worse on cognitive tests. Conclusions These preliminary data suggest a trend that paraquat may have differential effects depending on the task (cognitive vs. motor), and gclm -/- mice may be more susceptible to an oxidative stressor.