二十碳五烯酸对大鼠海马体突触可塑性、不饱和脂肪酸...
二十碳五烯酸对大鼠海马体突触可塑性、不饱和脂肪酸综合表现和磷酸肌醇3-激酶信号表达及对PC12细胞分化之影响
安慰剂对照临床研究表明， n-3多不饱和脂肪酸 （n-3 polyunsaturated fatty acids）能改善神经系统疾病 - 如阿尔茨海默氏病，亨廷顿氏症和精神分裂症等。为了评价二十碳五烯酸（eicosapentaenoic acid (EPA)） 的影响，我们给大鼠口服高纯度乙基二十碳五烯酸 （EPA-E），剂量为1.0毫克/克每天，然后测量海马CA1区长时程增强效应 - 一个普遍被认为是对学习和记忆等基础生理关联突触可塑性有关之区域。EPA-E组于CA1区域内之平均场兴奋性突触后电位斜率(mean fEPSP slope) 远远大于对照组。而且一个调节亚基磷酸肌醇3激酶（ PI3激酶）的子单元 （海马p85alpha）之基因表达量是随着EPA-E增加而增加的。对神经元和神经胶质的脂肪酸系列调查表明，单次注射EPA-E能大幅度增加神经元EPA和神经胶质EPA以及二十二碳六烯酸的量。这清楚地表明，EPA是被神经元和神经胶质细胞所吸收了。此外，我们研究了分化的PC12细胞中EPA对PI3-kinase/Akt通路的直接影响。经EPA处理过的细胞，磷酸化Akt表达量显著增加，神经生长因子退缩引导增加细胞死芒， 亦减少caspase-3活性。这些结果表明，EPA于防止神经退化的机制，是通过对突触可塑性的调控和激活PI3-kinase/Akt通路来进行的，具体机制可能是其自身作用于神经元和神经胶质细胞，及其增加脑二十二碳六烯酸的能力来完成的。
Effects of eicosapentaenoic acid on synaptic plasticity, fatty acid profile and phosphoinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells.
Kawashima A, Harada T, Kami H, Yano T, Imada K, Mizuguchi K.
Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, Jimba, Gotemba, Shizuoka 412-8524, Japan.
Placebo-controlled clinical studies suggest that intake of n-3 polyunsaturated fatty acids improves neurological disorders such as Alzheimer's disease, Huntington's disease and schizophrenia. To evaluate the impact of eicosapentaenoic acid (EPA), we orally administered highly purified ethyl EPA (EPA-E) to rats at a dose of 1.0 mg/g per day and measured long-term potentiation of the CA1 hippocampal region, a physiological correlate of synaptic plasticity that is thought to underlie learning and memory. The mean field excitatory postsynaptic potential slope of the EPA-E group was significantly greater than that of the control group in the CA1 region. Gene expression of hippocampal p85alpha, one of the regulatory subunits of phosphatidylinositol 3-kinase (PI3-kinase), was increased with EPA-E administration. Investigation of fatty acid profiles of neuronal and glia-enriched fractions demonstrated that a single administration of EPA-E significantly increased neuronal and glial EPA content and glial docosahexaenoic acid content, clearly suggesting that EPA was indeed taken up by both neurons and glial cells. In addition, we investigated the direct effects of EPA on the PI3-kinase/Akt pathway in differentiated PC12 cells. Phosphorylated-Akt expression was significantly increased in EPA-treated cells, and nerve growth factor withdrawal-induced increases in cell death and caspase-3 activity were suppressed by EPA treatment. These findings suggest that EPA protects against neurodegeneration by modulating synaptic plasticity and activating the PI3-kinase/Akt pathway, possibly by its own functional effects in neurons and glial cells and by its capacity to increase brain docosahexaenoic acid.
