Mechanism of Ischemic Neuronal Death : Neuron, Glial interaction

本研究旨在研究脑缺血后胶质细胞的活化和肝素结合生长相关分子的表达，以获得预防缺血性痴呆的线索。(1)胶质细胞应激激活分子的诱导缺血后小胶质细胞被激活，并呈现多种免疫反应分子。星形胶质细胞呈现应激蛋白，如HSP 27。缺血区中性粒细胞表达细胞粘附分子。这些数据表明，能够干预免疫过程的化学物质可能有望用于治疗缺血性脑损伤。(2)神经营养物质和缺血我们专注于肝素结合生长相关分子（HB-GAM），因为HB-GAM对各种类型的神经元显示出营养作用。我们观察到HB-GAM在正常海马CA 1区锥体神经元中有表达。缺血后海马CA 1区HB-GAM表达明显增强，反应性星形胶质细胞是HB-GAM的主要来源，HB-GAM受体Syndecan-3的表达也发生了变化。这些结果表明，HB-GAM可能在神经元存活和突触重排中起重要作用。盐酸双苯美仑（BF）是胆碱能系统的调节剂，并增加毒蕈碱胆碱能受体密度。缺血后用BF治疗100天的动物显示海马胆碱酯酶活性增加。因此，胆碱能系统的调节可能有利于缺血后脑功能障碍的治疗。

The present was designed to study (1) glial cell activation, and (2) heparin-binding growth-associated molecule exression after ischemia in order to obtain a clue to prevent ischemia-induced dementia.(1) Induction of stress-activated molecules in the glial cellsMicroglial cells were activated after ischemia and presented various immuno-reactive molecules. Astroglial cells presented stress proteins, such as HSP27. Neutrophils in ischemic areas expressed cell adhesion molecules. These data suggest that chemicals that can intervene immunological processes could be promissing for the treatment of ischemic brain injury.(2) Neurotrophic substances and ischemiaWe focused upon heparin-binding growth-associated molecules (HB-GAM), as HB-GAM shows trophic effects on various types of neurons. We observed that HB-GAM is expressesd in normal CA1 pyramidal neurons. After ischemic death of CA1 neuron, HB-GAM expression in the CA1 subfield was markedly enhanced and reactive astrocytes were the major source of HB-GAM.The level of Syndecan-3, the receptor for HB-GAM,was also altered after ischemia. These results suggest that HB-GAM may play an important role for neuronal survival and synaptic rearrangement.Bifemelane hydrochloride (BF) is a modulator of cholinergic systems and increases muscarinic cholinergic receptor density. Animals treated with BF for one-hundred days after ischemia showed increased cholinesterase activity in the hippocampus. Thus, modulation of cholinergic system could be beneficial for the treatment of post-ischemic brain dysfunction.