Estrogen and neuronal apoptosis -the molecular mechamism-

我们的前期研究表明，雌激素在较低浓度下可提高大鼠海马神经元的存活率，而糖皮质激素则相反。用抗雌激素受体单克隆抗体进行免疫组化研究，结果表明雌激素受体样免疫反应不仅在边缘系统，而且在大脑皮质的广泛区域均明显增强。这些结果也证实了通过原位杂交实验雌激素受体mRNA。雌激素注射之前，红藻氨酸诱导的神经营养因子及其mRNA的表达，如肝细胞生长因子，IGF I和II，观察斑点印迹分析，免疫组织化学以及原位杂交。在海人酸之前注射雌激素也能增加海马内GAP-43样免疫反应性。通过单独注射雌激素的实验，我们证实，当用凝胶迁移分析法观察时，雌激素增加AP-1-DNA结合活性，时间过程长达120分钟。这些结果表明，雌激素在神经元修复中起作用，并伴随着雌激素受体增加的连续过程。AP-1-DNA结合活性升高，诱导IGF I mRNA和GAP 43表达。

Our foregoing studies revealed that estrogen caused increase of the survival rate of rat hippocampal culture neurons at lower concentrations, contrary to the case of glucocorticoid. Basing on this result, 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. Estrogen injection prior to kainic acid also increased GAP43 like immunoreactities in the hippocampus.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 neuronl repair with successive processes of increased estrogen receptors, elevation of AP-1-DNA binding activity, induction of IGF I mRNA AND GAP43 expression.