CROSSTALKS AMONG SIGNAL TRANSDUCTION SYSTEMS IN APOPTOSIS IN RELATION WITH DEVELOPMENT DIFFERENTIATION AND AGING

雌激素不仅与神经元细胞的发育和分化密切相关，而且与损伤或老化神经元的修复机制密切相关。我们的前期研究发现，雌激素浓度为10^<-6>-10^<-9>时，可提高大鼠海马培养神经元的存活率，而浓度越高，则使其存活率降低。在此基础上，探讨了雌激素对凯尼克酸损伤脑的神经保护作用机制。使用雌激素受体单克隆抗体的免疫组化研究表明，雌激素受体样免疫反应性不仅在边缘系统显著增加，而且在大脑皮质的广泛区域也明显增加。雌激素受体mRNA的原位杂交实验也证实了这一结果。通过点印迹分析、免疫组织化学和原位杂交观察，在全身给药前注射雌激素可诱导神经营养因子及其mrna（如HGF、IGF I和II）的表达。通过单次注射雌激素的单独实验，我们证实了通过凝胶移位法观察，雌激素增加AP-1-DNA结合活性的时间可达120分钟。这些结果表明，雌激素在神经元修复中的作用是通过增加雌激素受体、提高AP-1-DNA结合活性、诱导IGF -1 mRNA的连续过程进行的。NGF诱导神经分化的PC12细胞具有雌激素受体。我们注意到雌激素与NGF共同作用可延长PC12细胞的存活率。

Estrogen is deeply associated not only with development and differentiational of neuronal cells, but also with rescue mechanisms of injured or aging neurons. Our foregoing studies revealed that estrogen caused increase of the survival rate of rat hippocampal culture neurons at concentrations of 10^<-6>-10^<-9>, while depressed the survival at higher concetrations. Basing on these results, mechanisms of neuroprotective effects of estrogen were studied on kainic acid-injured brains.Immunohistochemical studies with use of monoclonal antibody against estrogen receptor showed marked increase of estrogen receptor-like immunoreactivities not only in the limbic system, but also in the wide areas of the cerebral cortesses. Such results were also confirmed through in situ hybridization experiments for estrogen receptor mRNA.Estrogen injection prior to a systemic administration of kainic acid-induced expression of neurotrophic factor and their mRNAs such as HGF,IGF I and II,as observed by dot blotting analysis, immunohistochemistry as well as in situ hybridization.Through a separate experiment with single injection of estrogen, we confirmed that estrogen increased AP-1-DNA binding activity with time course up to 120 min. when observed by gel shift assay method.These results suggested that estrogen playd roles in neuronal repair with successive proceses of increased estrogen receptors, elevation of AP-1-DNA binding activity, induction of IGF I mRNA.Neuronally differentiated PC12 cells by NGF have estrogen receptors. We noticed estrogen lenpthened the survival of PC12 cells when added together with NGF.