Submitted to: American Aging Association
Publication Type: Peer reviewed journal
Publication Acceptance Date: 5/23/2007
Publication Date: 9/25/2007
Citation: Denissova, N., Rosenberg, I., Shukitt Hale, B., Bielinski, D., Dallal, G., Joseph, J.A. 2007. Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide. American Aging Association. 29:191-203. Interpretive Summary: Our previous studies demonstrated a significant decrease in brain activity and behavior in rats with age. The present study was designed to test the hypothesis that disruption in calcium flux may contribute to the increase in age-related sensitivity to stress in the brain with a subsequent changes in brain functions. Samples were isolated from the different areas of the brain and were assessed for calcium dynamics and brain signaling under control and stress conditions. Stress conditions were induced by low dose hydrogen peroxide. The level of stress responses was monitored by measuring damaging and protective components in the brain areas. The results showed a significant difference in stress responses between young and old rats in evaluated brain areas. Old rats showed higher sensitivity to stress than young rats. The present findings show that the difference in calcium flux between young and old rats are dependent upon the brain areas examined and the purity of the brain samples assessed. This is the first study, to our knowledge, that demonstrates the difference in sensitivity to stress between different brain areas with age.
Technical Abstract: Our previous studies demonstrated a significant decline in brain function and behavior in Fischer 344 (F344) rats with age. The present study was designed to test the hypothesis that dysregulation in calcium homeostasis (as assessed through 45Ca flux) may contribute to the increase in age-related vulnerability to oxidative stress in brain regions, and result in a deficit in behavior-mediated signaling. Crude membrane (P-2) and more purified synaptosomal fractions were isolated from the striatum, hippocampus, and frontal cortex of young (6 mo) and old (22 mo) F344 rats and were assessed for calcium flux and extracellular-regulated kinase activity 1 (ERK) under control and oxidative stress conditions induced by low dose hydrogen peroxide (final conc. 5 uM). The level of oxidative stress responses was monitored by measuring reactive oxygen species (ROS) and glutathione (GSH). The results showed a significant difference in oxidative stress responses between young and old rats in evaluated brain regions. Old rats showed higher sensitivity to oxidative stress than young rats. The present findings show the differential effects of oxidative stress on calcium flux in brain regions with age that are dependent upon the brain areas examined and the fraction assessed. The accumulation of ROS and the decrease in GSH in the frontal cortex were sufficient to decrease ERK activity in old rats. This is the first study, to our knowledge, that demonstrates age-related differential sensitivity to oxidative stress expressed as a function of behavior-mediated signaling and stress levels among different fractions isolated from brain regions controlling behavior.