Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide
Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide
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DOI：
10.1007/s11357-007-9039-7
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发表时间：
2007-12-01
期刊：
影响因子：
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通讯作者：
Joseph, James A.
中科院分区：
文献类型：
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作者：
Crivello, Natalia A.;Rosenberg, Irwin H.;Joseph, James A.
我们之前的研究表明，Fischer 344(F344)大鼠的大脑功能和行为随着年龄的增长而显著下降。本研究旨在验证一种假说，即钙稳态失调(通过Ca-45通量评估)可能导致大脑区域与年龄相关的氧化应激易感性增加，并导致行为中介信号的缺陷。从青年(6月龄)和老年(22月龄)F344大鼠的纹状体、海马和额叶皮质分离粗膜(P-2)和纯化的突触体组分，并在对照组和低剂量过氧化氢(终浓度为5mM)诱导的氧化应激条件下，评估钙离子通量和细胞外调节蛋白激酶活性1(ERK)的变化。通过测定活性氧(ROS)和谷胱甘肽(GSH)来监测氧化应激反应水平。结果显示，在被评估的大脑区域，年轻和老年大鼠的氧化应激反应存在显著差异。老年大鼠对氧化应激表现出比青年大鼠更高的敏感性。目前的发现表明，氧化应激对大脑区域钙流动的不同影响与年龄有关，这取决于所检查的大脑区域和评估的比例。额叶皮质中ROS的积聚和GSH的减少足以降低老年大鼠ERK的活性。据我们所知，这是第一项研究表明，从控制行为的大脑区域分离出来的不同部分，对氧化应激的年龄相关差异敏感性，表现为行为介导的信号和应激水平的函数。
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 Ca-45 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 months) and old (22 months) 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 concentration 5 mu M). 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.