Research and Development of Neuroprotective Drugs Targeted for Glial Cells

内皮素受体激动剂对培养星形胶质细胞神经营养因子产生的影响：损伤后神经系统的再生是由星形胶质细胞产生的神经营养物质支持的。在这项研究中，我们检测了内皮素-1 （ET-1）受体激动剂对星形胶质细胞中神经营养因子产生的影响，内皮素-1在损伤脑中增加。ET-1刺激培养的星形胶质细胞中胶质细胞系源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的表达。大鼠脑内注入ET受体激动剂可增加海马GDNF mRNA和蛋白水平。尾状壳核和大脑中BDNF的表达也因ET激动剂而增加。培养的星形胶质细胞具有含有外显子3和外显子4的BDNF转录本，但不含外显子1和外显子2转录本。ET-1处理增加了含有BDNF的外显子3和外显子4的转录本。et诱导的星形细胞BDNF转录检测显示，DNF基因外显子3是由ERK和creb介导的机制诱导的。BDNF基因外显子4被证明是由C/ ebp β介导的机制介导的。这些结果提示ET受体可能是神经营养药物的靶点。新型神经营养药物的作用机制：T-588是一种具有营养保护作用的脐药，可引起大鼠海马Erk活化。此外，我们发现在动物模型中具有认知增强作用的FK960刺激了培养的大鼠星形胶质细胞中GDNF的产生。新型神经营养药物的这些作用可能是其药理作用的基础。

Effects of Endothelin Receptor Agonists on Neurotrophic Factor Production in cultured Astrocytes: Re-generation of nervous systems after injury is supported by neurotrophic substances produced by astrocytes. In this study, we examined effects of a receptor agonist of endothelin-1 (ET-1), which increased in damages brain, on neurotrophic factor production in astrocytes. ET-1 stimulated expressions of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in cultured astrocytes. Intracerebroventircular administration of an ET receptor agonist Into rat brain increases both mRNA and protein levels of GDNF in hippocampus. BDNF expression in caudate putamen and cerebrum also increased by the ET agonist. Cultured astrocytes had exon 3 and exon 4-containing BDNF transcripts, but not exon 1 and exon 2 transcripts. Treatment with ET-1 increased both exon 3 and exon 4-containing BDNF transcripts. Examinations on ET-induced astrocytic BDNF transcription showed that the exon 3 of DNF gene were induced by ERK and CREB-mediated mechanisms. The exon 4 BDNF gene was shown to be mediated by C/EBPβ-mediated mechanisms. These results suggest that ET receptors are possible target of neurotrophic drugs.Mechanisms of novel neurotrophic drugs: T-588, a navel drug showing nouroprotective actions, caused Erk activation in rat hippocampus. Also, we found FK960, which have cognitive enhancing actions in animal models, stimulated GDNF production in rat cultured astrocytes. These actions of novel neurotrophic drugs may underlie their phsrmacological actions.