Growth hormone administration to aged animals reduces disulfide glutathione levels in hippocampus
Growth hormone administration to aged animals reduces disulfide glutathione levels in hippocampus
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DOI：
10.1016/j.mad.2005.09.003
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发表时间：
2006-01-01
影响因子：
5.3
通讯作者：
Sonntag, WE
中科院分区：
文献类型：
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作者：
Donahue, AN;Aschner, M;Sonntag, WE
全身生长激素 (GH) 和胰岛素样生长因子-1 (IGF-1) 是强效合成代谢激素，会随着年龄的增长而减少。在人类和动物模型中，对老年受试者施用生长激素或 IGF-1 可以改善学习和记忆，这表明与年龄相关的认知能力下降部分是由于外周 GH/IGF-1 缺乏所致。然而，GH/IGF-1 影响认知功能的细胞机制尚不清楚。我们认为这些激素的作用可能是通过增加细胞氧化还原电位从而减少氧化应激来介导的。由于最丰富的内源性抗氧化剂是谷胱甘肽 (GSH)，我们评估了用猪生长激素（200 微克/动物，每天两次）或媒介物治疗的年轻（4 个月大）和老年（30 个月大）雄性 Fisher 344 x Brown 挪威大鼠海马体和额叶皮层中的 GSH 和二硫化物谷胱甘肽 (GSSH) 水平。我们报告海马 GSSG 水平随着年龄的增长而增加（0.54 +/- 10.08 至 1.55 +/- 0.24 nmol GSSG/mg 蛋白，p < 0.05），并且生长激素治疗改善了 GSSG 与年龄相关的升高（1.55 +/- 0.24 至 0.87 +/- 0.24 nmol GSSG/mg 蛋白，p < 0.05）以及 GSH/GSSG 比率的下降。对老年动物 GSSG 还原酶活性的分析表明，年龄或生长激素治疗没有影响 (p = 0.81)。尽管额叶皮层中 GSSG 与年龄相关的增加和 GSH/ GSSG 比率的减少相似，但生长激素没有影响。随后，我们评估了年龄和生长激素治疗的影响是否是由调节微量金属积累引起的。通过电感耦合等离子体质谱法分析了海马体和额叶皮质中的 13 种金属。铝、铜、铁、锰和锌的水平随着年龄的增长而增加（p < 0.05），但生长激素替代对金属积累没有影响。我们的结果表明，生长激素替代可以减轻海马中与年龄相关的氧化应激增加，而不影响谷胱甘肽还原酶或微量金属积累。我们得出的结论是，循环生长激素和 IGF-1 与年龄相关的下降导致海马氧化应激随着年龄的增长而增加。 (c) 2005 Elsevier Ireland Ltd. 保留所有权利。
Systemic growth hormone (GH) and insulin-like growth factor-1 (IGF-1), potent anabolic hormones, decrease with age. In humans and animal models, administration of growth hormone or IGF-1 to aged subjects improves learning and memory, suggesting that the age-related decline in cognitive performance results, in part, from peripheral GH/IGF-1 deficiency. However, the cellular mechanisms by which GH/IGF-1 effect cognitive function are unknown. We propose that the effects of these hormones may be mediated by increasing cellular redox potential resulting in reduced oxidative stress. Because the most abundant endogenous antioxidant is glutathione (GSH), we assessed GSH and disulfide glutathione (GSSH) levels in hippocampus and frontal cortex of young (4-month-old) and aged (30-month-old) male Fisher 344 x Brown Norway rats treated with porcine growth hormone (200 mu g/animal, twice/daily) or vehicle. We report that hippocampal levels of GSSG increase with age (0.54 +/- 10.08 to 1.55 +/- 0.24 nmol GSSG/mg protein, p < 0.05) and growth hormone treatment ameliorates both the age-related rise in GSSG (1.55 +/- 0.24 to 0.87 +/- 0.24 nmol GSSG/mg protein, p < 0.05) and the decline in GSH/GSSG ratios. Analysis of GSSG reductase activity in aged animals indicated no effect of either age or growth hormone treatment (p = 0.81). Although similar age-related increases in GSSG and decreases in GSH/ GSSG ratios were evident in frontal cortex, growth hormone had no effect. Subsequently, we assessed whether the effects of age and growth hormone treatment result from modulating trace metal accumulation. Thirteen metals were analyzed in hippocampus and frontal cortex by inductive coupled plasma mass spectrometry. Aluminum, copper, iron, manganese and zinc levels increased with age (p < 0.05 each) but growth hormone replacement had no effect on metal accumulation. Our results indicate that growth hormone replacement attenuates the age-related increase in oxidative stress in hippocampus without effects on glutathione reductase or trace metal accumulation. We conclude that the age-related decline in circulating growth hormone and IGF-1 contribute to increased oxidative stress in hippocampus with age. (c) 2005 Elsevier Ireland Ltd. All rights reserved.