Oxidative impairment of hippocampal long-term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodies.
Oxidative impairment of hippocampal long-term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodies.
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DOI：
10.1002/jnr.21782
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发表时间：
2008-11-15
影响因子：
4.2
通讯作者：
Rho, Jong M.
中科院分区：
文献类型：
--
作者：
Maalouf, Marwan;Rho, Jong M.
先前的研究表明，酮体（KB）在神经系统疾病的实验模型中具有抗氧化作用。本研究采用电生理、荧光成像和酶分析技术，探讨了乙酰乙酸KB （ACA）和β-羟基丁酸β (BHB)对过氧化氢（H2O2）对大鼠海马长期增强（LTP）损伤的影响。我们发现：(1)ACA和BHB（各1 mM）可防止H2O2 （200 μM）对LTP的损伤；(2) KB显著降低H2O2暴露的CA1锥体神经元细胞内活性氧（ROS）水平（用荧光指示剂carboxy-H2DCFDA测定）；(3) KB对LTP的影响被蛋白磷酸酶2A （PP2A）抑制剂fostriecin复制；(4) KB通过PP2A激活剂C6神经酰胺阻止LTP损伤；(5) fostriecin不能阻止H2O2作用下CA1锥体神经元中ROS水平的升高，C6神经酰胺不能增加ROS水平；(6) h2o2和鱼藤酮（一种线粒体复合体I抑制剂，可增加内源性超氧化物生成）均可增强PP2A活性；(7) KB抑制H2O2或神经酰胺处理脑组织蛋白提取物的PP2A活性。我们认为海马LTP的氧化损伤与PP2A的激活有关，KB通过抗氧化机制诱导PP2A抑制，部分地阻止了这种损伤。
Previous studies have shown that ketone bodies (KB) exert antioxidant effects in experimental models of neurological disease. In the present study, we explored the effects of the KB acetoacetate (ACA) and β-hydroxybutyrate (BHB) on impairment of hippocampal long-term potentiation (LTP) in rats by hydrogen peroxide (H2O2) using electrophysiological, fluorescence imaging and enzyme assay techniques. We found that: (1) a combination of ACA and BHB (1 mM each) prevented impairment of LTP by H2O2 (200 μM); (2) KB significantly lowered intracellular levels of reactive oxygen species (ROS) — measured with the fluorescent indicator carboxy-H2DCFDA — in CA1 pyramidal neurons exposed to H2O2; (3) the effect of KB on LTP was replicated by the protein phosphatase 2A (PP2A) inhibitor fostriecin; (4) KB prevented impairment of LTP by the PP2A activator C6 ceramide; (5) fostriecin did not prevent the increase in ROS levels in CA1 pyramidal neurons exposed to H2O2, and C6 ceramide did not increase ROS levels; (6) PP2A activity was enhanced by both H2O2and rotenone – a mitochondrial complex I inhibitor that increases endogenous superoxide production; and (7) KB inhibited PP2A activity in protein extracts from brain tissue treated with either H2O2 or ceramide. We propose that oxidative impairment of hippocampal LTP is associated with PP2A activation, and that KB prevent this impairment in part by inducing PP2A inhibition through an antioxidant mechanism.
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DOI：
10.1073/pnas.97.10.5440
发表时间：
2000-05-09
影响因子：
11.1
作者：
Kashiwaya, Y;Takeshima, T;Veech, RL
通讯作者：
Veech, RL
影响因子：
2.2
作者：
LAMERS, KJB;GABREELS, FJM;DOESBURG, WH
通讯作者：
DOESBURG, WH
DOI：
10.1016/s0169-328x(00)00088-7
发表时间：
2000-05-31
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Eckles-Smith, K;Clayton, D;Browning, MD
通讯作者：
Browning, MD
影响因子：
1.7
作者：
HORI, N;HIROTSU, I;CARPENTER, DO
通讯作者：
CARPENTER, DO
影响因子：
2.9
作者：
HYSLOP, PA;ZHANG, ZY;PHEBUS, LA
通讯作者：
PHEBUS, LA