Investigation of therapy for neonatal hypoxic-ischemic brain damage

新生儿缺氧缺血性脑损伤的治疗研究

• 批准号: 12470345
• 负责人: IKENOUE Tsuyomu
• 金额: $ 5.06万
• 依托单位: 宮崎医科大学
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470345/
• 关键词: hypoxic-ischemic brain damage; glial cell line-derived neurotrophic facto; rat; neonate; glucocorticoid; brachial plexus injury; cerebrospinal fluid; 低酸素性虚血性脳障害; グリア細胞由来神経栄養因子; 低酸素虚血脳症; 記憶学習障害; 神経栄養因子

Glial cell line-derived neurotrophic factor (GDNF) was discovered as a potent neurotrophic factor to the dopaminergic neurons in the midbrain at 1993. The subsequent studies revealed its trophic effect on the motor neuron and beneficial effect on brain edema. We have investigated the involvement of GDNF in neonatal hypoxic-ischemic brain damage as follows.(1) Intraparenchymal administration of 2μg and 4μg of GDNF provided remarkable protection against ischemia/hypoxia-induced brain damage in 7-day-old rats in a dose-dependent manner.(2) Expression of GDNF in developing rat brain form post natal day (PND) 1 to 14 and on PND 21 was examined immunocytochemically. The results revealed the characteristic developmental shifts in GDNF expression in neuronal and non-neuronal cells, which indicated that GDNF may be of critical importance at different stages of brain growth and differentiation. ELISA of the cerebrospinal fluid (CSF) revealed a rapid rise in GDNF levels from PND 1 to peak levels at PND 7-9, and thereafter, the levels gradually decreased.(3) In hypoxic-ischemic brain damage model of 7-day-old rat, brain GDNF levels took two peak, 3 and 48 hours after the insult. Immunocytochemical study showed that the former peak was represented by GDNF production in neurons and the latter peak was corresponded by that in migrating astrocytes.(4) Administration of dexamethasone (0.5 mg/kg) for 3 days beginning from PND 1 significantly increased GDNF levels in the CSF at PND 3-5. However, GDNF levels in the CSF in the group which receive dexamethasone in the early life were lower than that in the control group at PND 10.(5) We established the neonatal rat model mimicking upper brachial plexus palsy in newborn, in which the behavioral and histological changes could be evaluated. Topical application of gelform soaked with 4μg of GDNF dramatically improved the behavioral and histological impairment.

胶质细胞源性神经营养因子（glialcellline-derivedneurotrophicfactor，GDNF）是1993年发现的一种对中脑多巴胺能神经元有重要作用的神经营养因子。随后的研究显示其对运动神经元的营养作用和对脑水肿的有益作用。我们研究了GDNF在新生儿缺氧缺血性脑损伤中的作用，如下。(1)脑实质内注射2μg和4μg GDNF对7日龄大鼠缺血/缺氧性脑损伤具有明显的保护作用，且呈剂量依赖性。(2)用免疫细胞化学方法检测了GDNF在纳塔尔后1 ~ 14天和出生后21天大鼠脑发育过程中的表达。结果揭示了GDNF在神经元和非神经元细胞中表达的特征性发育变化，这表明GDNF可能在脑生长和分化的不同阶段至关重要。脑脊液（CSF）的ELISA显示GDNF水平从PND 1迅速上升至PND 7-9的峰值水平，此后，水平逐渐下降。(3)在7日龄大鼠缺氧缺血性脑损伤模型中，脑内GDNF含量在伤后3小时和48小时出现两个高峰。免疫细胞化学研究表明，前一个峰是神经元中GDNF的产生，后一个峰是迁移性星形胶质细胞中GDNF的产生。(4)从PND 1开始给予地塞米松（0.5mg/kg）3天显著增加PND 3-5时CSF中的GDNF水平。然而，在出生后第10天，在早期接受地塞米松的组的CSF中GDNF水平低于对照组。(5)本研究建立了模拟新生大鼠上臂丛神经麻痹的动物模型，观察了新生大鼠上臂丛神经麻痹的行为学和组织学变化。局部应用4μ gGDNF浸泡的凝胶剂显著改善了行为学和组织学损害。

项目成果

K.Nagai: "Effects of actinomycin D on fetal growth"The Journal of Maternal-Fetal Medicine. 10(2). 136-140 (2001)

K.Nagai：“放线菌素 D 对胎儿生长的影响”母胎医学杂志。

Snigeru Fukamachi, Akiko Furuta, Tomoaki Ikeda, Tsuyomu Ikenoue , Tsuyoshi Kaneoka, Jeffery D. Rothstein, Toru Iwaki: "Altered expressions of glutamate transporter subtypes in rat model of neonatal cerebral hypoxia-ischemia"Brain Res Dev Brain Res. 132(2)

Snigeru Fukamachi、Akiko Furuta、Tomoaki Ikeda、Tsuyomu Ikenoue、Tsuyoshi Kaneoka、Jeffery D. Rothstein、Toru Iwaki：“新生儿脑缺氧缺血大鼠模型中谷氨酸转运蛋白亚型的表达改变”Brain Res Dev Brain Res。

Tomoaki Ikeda: "Selective and long-termlearning impairment following neonatal hypoxic-ischemic brain insult in rats"Behavioural Brain Research. 118. 17-25 (2001)

Tomoaki Ikeda：“大鼠新生儿缺氧缺血性脑损伤后的选择性和长期学习障碍”行为脑研究。

Hiroshi Sameshima: "Long-term magnesium sulfate treatment as protection against hypoxic-ischemic brain injury in seven-day-old rats"Am.J.Obstet.Gynecol. 184. 185-190 (2001)

Hiroshi Sameshima：“长期硫酸镁治疗可预防 7 日龄大鼠缺氧缺血性脑损伤”Am.J.Obstet.Gynecol。

Masatoki Kaneko,Hiroshi Sameshima,Tomoaki Ikeda,Yaki Kodama,and Tsuyoma Ikenoue: "Antepartum Evaluation of Monochorionic Diamniotic (MD) Twins ; MD-Twin Score : A New Sooring Method for Perinatal Outcome"The Journal of Obstetrics and Gynaecology Research.

Masatoki Kaneko、Hiroshi Sameshima、Tomoaki Ikeda、Yaki Kodama 和 Tsuyoma Ikenoue：“单绒毛膜双羊膜 (MD) 双胞胎的产前评估；MD-双胞胎评分：围产期结果的新排序方法”妇产科研究杂志。