二十碳五烯酸對大鼠海馬體突觸可塑性、不飽和脂肪酸綜合表現(xiàn)和磷酸肌醇3-激酶信號表達及對PC12細胞分化之影響
二十碳五烯酸對大鼠海馬體突觸可塑性、不飽和脂肪酸綜合表現(xiàn)和磷酸肌醇3-激酶信號表達及對PC12細胞分化之影響
安慰劑對照臨床研究表明， n-3多不飽和脂肪酸 （n-3 polyunsaturated fatty acids）能改善神經系統(tǒng)疾病 - 如阿爾茨海默氏病，亨廷頓氏癥和精神分裂癥等。為了評價二十碳五烯酸（eicosapentaenoic acid (EPA)） 的影響，我們給大鼠口服高純度乙基二十碳五烯酸 （EPA-E），劑量為1.0毫克/克每天，然后測量海馬CA1區(qū)長時程增強效應 - 一個普遍被認為是對學習和記憶等基礎生理關聯(lián)突觸可塑性有關之區(qū)域。EPA-E組于CA1區(qū)域內之平均場興奮性突觸后電位斜率(mean fEPSP slope) 遠遠大于對照組。而且一個調節(jié)亞基磷酸肌醇3激酶（ PI3激酶）的子單元 （海馬p85alpha）之基因表達量是隨著EPA-E增加而增加的。對神經元和神經膠質的脂肪酸系列調查表明，單次注射EPA-E能大幅度增加神經元EPA和神經膠質EPA以及二十二碳六烯酸的量。這清楚地表明，EPA是被神經元和神經膠質細胞所吸收了。此外，我們研究了分化的PC12細胞中EPA對PI3-kinase/Akt通路的直接影響。經EPA處理過的細胞，磷酸化Akt表達量顯著增加，神經生長因子退縮引導增加細胞死芒， 亦減少caspase-3活性。這些結果表明，EPA于防止神經退化的機制，是通過對突觸可塑性的調控和激活PI3-kinase/Akt通路來進行的，具體機制可能是其自身作用于神經元和神經膠質細胞，及其增加腦二十二碳六烯酸的能力來完成的。
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.
