ANALYSIS OF MULTIFUNCTION OF MICROGLIA IN THE ISCHEMIA-RELATED NEURONAL DEATH

小胶质细胞在缺血相关神经元死亡中的多功能分析

基本信息

批准号：
13670090
负责人：
SAKURAI Yasuko
金额：
$ 2.24万
依托单位：
NAGASAKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670090/
关键词：
ISCHEMIA-RELATED NEURONAL DEATH MICROGLIA ASTROCYTES MCP-1 ET_B RECEPTOR BLOOD BRAIN BARRIER

项目摘要

We have studied the mechanism of ischemia-related neuronal death leading to dementia. Our previous results demonstrated that microglia expressing endothelin ETB (ETB) receptor aggregated in the pyramidal layer of the hippocampus where the selective neuronal death occurred. We tried to induce ischemia in the spotting lethal (sl) rats with lack of the ETB gene expression. As the rats homozygous for this mutation die shortly due to the congenital distal aganglionosis, they were legated an unilateral carotid artery and exposed to hypoxia at 2 weeks old according to the neonatal ischemia model. The ipsilateral pyramidal cells were lost in both ETB^<+/+> and ETB^<sl/sl> and the process was different from that in SHRSP because of the clear histochemical damage at 24h after reperfusion in the neonatal model. Then we investigated the expression of monocyte chemoattractant protein-1 (MCP-1) because our previous study showed the increased permeability of blood brain barrier (BBB) at 24h after the ischemia-reperfusion in SHRSP. MCP-1 mRNA was expressed in the astrocytes of dentate gyrus at 24h after 10 min-ischemia and distributed in the CA1 subfield at 48h. The expressing cells at 48h in the CA1 subfield was almost astrocytes. Increased MCP-1 protein concentration was also demonstrated in the hippocampus at 48h by ELISA. Cultured astrocytes were used to clarify the induction of MCP-1 after the in vitro ischemic condition, aglycemia/hypoxia by astrocytes themselves. Expression of MCP-1 mRNA was dramatically increased in the astrocytes from SHRSP, however a little in those from WKY, normotensive rats. These results suggest that MCP-1 expressed in astrocytes after the ischemia-reperfusion might make monocytes migrate into the brain and also activate microglia. The substances to inhibit the secretion or function of MCP-1 could inhibit the delayed neuronal death induced by a transient global ischemia in SHRSP.

我们研究了与缺血有关的神经元死亡的机制，导致痴呆症。我们先前的结果表明，表达内皮素ETB（ETB）受体的小胶质细胞聚集在发生选择性神经元死亡的海马层中。我们试图在缺乏ETB基因表达的情况下诱导致命（SL）大鼠的缺血。由于先天性远端的arganglioniso，由于新生儿缺血模型，由于先天性远端的大鼠纯合子死亡，因此它们被延长了单侧颈动脉，并在2周大时暴露于缺氧。同侧锥体细胞在ETB^<+/+>和etb^<sl/sl>中都丢失了，由于新生儿模型的再灌注后24小时，该过程与SHRSP中的过程不同。然后，我们研究了单核细胞化学吸引蛋白-1（MCP-1）的表达，因为我们先前的研究表明，SHRSP中缺血 - 重新灌注后24H时血液脑屏障（BBB）的渗透性增加。在10分钟 - 异常后，在24小时内在齿状回的星形胶质细胞中表达MCP-1 mRNA，并在48h时分布在CA1子场中。 CA1子场48h处的表达细胞几乎是星形胶质细胞。 ELISA在48h时在海马中也证明了MCP-1蛋白浓度的增加。培养的星形胶质细胞用于阐明体外缺血状态，星形胶质细胞本身的良性良性/低氧症状后MCP-1的诱导。在SHRSP的星形胶质细胞中，MCP-1 mRNA的表达显着增加，但是WKY，正常的大鼠的表达有所增加。这些结果表明，缺血 - 重新灌注后在星形胶质细胞中表达的MCP-1可能会使单核细胞迁移到大脑中并激活小胶质细胞。抑制MCP-1分泌或功能的物质可以抑制SHRSP中瞬时全局缺血引起的延迟神经元死亡。