Resveratrol stimulates AMP kinase activity in neurons
Resveratrol stimulates AMP kinase activity in neurons
复制标题
DOI：
10.1073/pnas.0610068104
复制
发表时间：
2007-04-24
影响因子：
11.1
通讯作者：
Milbrandt, Jeffrey
中科院分区：
文献类型：
--
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
白藜芦醇是一种由植物产生的多酚，具有与热量限制（CR）相关的多种有益活性，例如延长寿命和延迟与衰老相关的疾病的发作。CR改善神经元健康，并且CR的总体有益作用已被假定为由神经系统介导。在CR过程中被激活的一种关键酶是AMP激活的激酶（AMPK），它是细胞能量水平的传感器。AMPK通过细胞AMP：ATP比率的增加而被激活，因此它的功能是帮助保存细胞能量。在这方面，下丘脑神经元对饮食食物摄入的调节是由AMPK介导的。通过激活AMPK沿着白藜芦醇的CR模拟和神经保护特性抑制非必需能量消耗，使我们假设AMPK的神经元激活可能是白藜芦醇活性的重要组成部分。在这里，我们表明，白藜芦醇激活AMPK在Neuro 2a细胞和原代神经元在体外以及在大脑中。白藜芦醇和AMPK激活化合物5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）促进Neuro 2a细胞中神经突的生长，这被AMPK的遗传和药理学抑制所阻断。白藜芦醇也刺激线粒体生物合成的AMPK依赖的方式。白藜芦醇刺激的神经元中AMPK活性依赖于LKB 1活性，但在此时间范围内不需要NAD依赖性蛋白脱乙酰酶SIRT 1。这些结果表明，神经元激活AMPK的白藜芦醇可能会影响神经元的能量稳态，并有助于白藜芦醇的神经保护作用。
Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.