Hypoxic-ischemic tolerance in newborn rat brain

新生大鼠脑缺氧缺血耐受性

• 批准号: 11671071
• 负责人: IKEDA Tomoaki
• 金额: $ 0.45万
• 依托单位: Miyazaki Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671071/
• 关键词: hypoxic-ischemic tolerance; hyperthermia; heat shock protein; endotherium; blood brain barrier; cerebrospinal fluid; newborn; rat; 神経栄養因子

Understanding the endogenous neuroprotective mechanism is important for the prevention and treatment of hypoxic-ischemic brain damage in fetus and neonate, a major cause of childhood handicaps. We found the sublethal hypoxic or hypoerthermic preconditioning of 7-day-old rats reduced the severity of brain injury produced by subsequent hypoxic-ischemic stress. We named this phenomenon "hypoxic-ichemic tolerance" (Ota et al. Am J Obstet Gynecol 1998 ; 179 : 1075-8, Ota et al. Journal of SGI 2000 ; 102-5).Hyperhtermia-induced hypoxic-ischemic tolerance was observed at 6, 12, and 24 hours but not at 48 and 72 hours after hyperthermic preconditioning. Heat shock protein 72 expression in the vascular endothelial cells, rather than in the glial or neuronal cells, was most strongly associated with hypoxic-ischemic tolerance. Hyperhtermic preconditioning prevents disruption of blood-brain barrier, resulting in amelioration of hypoxic-ischemic neuronal damage. Taking all above mentioned results into account, "hypoxic-ischemic tolerance" seems to associate with the endothelial functional change in immature brain.As another endogenous protection mechanism, we started to investigate the role of neurotrophic factors. Cerebrospinal fluid concentration of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 was measured in normal developing rat from birth to postnatal day 21 by enzyme-linked immunosorbent assay. Expression of glial cell line-derived neurotrophic factor(GDNF) in developing rat brain from postnatal day 1 to 21 was examined immunocytochemiscally. GDNF injecting into brain parenchyma provided remarkable protection against ischemic-hypoxic-induced brain damage in 7-day-old rats in a dose-dependent manner.

了解内源性神经保护机制对于预防和治疗胎儿和新生儿缺氧缺血性脑损伤是重要的，缺氧缺血性脑损伤是儿童残疾的主要原因。我们发现，亚致死量的缺氧或低温预处理的7日龄大鼠降低了脑损伤的严重程度所产生的后续缺氧缺血应激。我们将这种现象命名为“缺氧缺血耐受性”（Ota等，Am J Obstet Gynecol 1998 ; 179：1075-8，Ota等，Journal of SGI 2000 ; 102-5）。在高温预处理后6、12和24小时观察到高温诱导的缺氧缺血耐受性，但在48和72小时未观察到。热休克蛋白72在血管内皮细胞中的表达，而不是在神经胶质细胞或神经元细胞中的表达，与缺氧缺血耐受性密切相关。高温预处理可防止血脑屏障的破坏，从而改善缺氧缺血性神经元损伤。综上所述，“缺氧缺血耐受”可能与未成熟脑的内皮功能改变有关，作为另一种内源性保护机制，我们开始研究神经营养因子在其中的作用。用酶联免疫吸附法测定了正常发育大鼠从出生到出生后21天脑脊液中神经生长因子、脑源性神经营养因子和神经营养因子-3的浓度。用免疫细胞化学方法检测了生后1 ~ 21天大鼠脑内胶质细胞源性神经营养因子（GDNF）的表达。脑实质内注射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。

项目成果

Ota A,Ikeda T,Xia XY,Xia YX,Ikenoue T.: "Hypoxic-ischemic tolerance induced by hyperthermic pretreatment in newborn rats."J Soc Gynecol Investig. 7(2). 102-105 (2000)

Ota A，Ikeda T，Xia XY，Xia YX，Ikenoue T.：“新生大鼠高温预处理诱导的缺氧缺血耐受性。”J Soc Gynecol Investig。

Xia YX,Ikeda T,Xia XY,Ikenoue T.: "Differential neurotrophin levels in cerebrospinal fluid and their changes during development in newborn levels."Neuroscience Letters. 280. 220-222 (2000)

Xia YX，Ikeda T，Xia XY，Ikenoue T.：“脑脊液中不同的神经营养蛋白水平及其在新生儿发育过程中的变化。”神经科学快报。

Arturo Ota,MD,Tomoaki Ikeda,MD,Xiao Y.Xia,MD,Yix.xia,MD,and Tsuyomu Ikenoue,MD: "Hypoxic-Ischemic Tolerance Induced by Hyperthermic Pretreatment in Newborn Rats."J.Soc Gynecol Investig. 7・2. 102-105 (2000)

Arturo Ota（医学博士）、Tomoaki Ikeda（医学博士）、Xiao Y.Xia（医学博士）、Yix.xia（医学博士）和 Tsuyomu Ikenoue（医学博士）：“新生儿热预处理诱导的缺氧缺血耐受性 J.Soc Gynecol 调查”。 2. 102-105（2000）

Ikeda T, Ikenoue T, Xia XY, Xia YX.: "Important role of 72-kd heat shock protein expression in the endothelial cell in acquisition of hypoxic-ischemic tolerance in the immature rat."Am J Obstet Gynecol. 182. 380-6 (2000)

Ikeda T、Ikenoue T、Xia XY、Xia YX.：“内皮细胞中 72-kd 热休克蛋白表达在未成熟大鼠获得缺氧缺血耐受性中的重要作用。”Am J Obstet Gynecol。

Tomoaki Ikeda,MD,Tsuyoma Ikenoue,MD,Xiao Y.Xia,MD,and Yix.Xia,MD: "Important role of 72-kd heat shock protein expression in the endothelial cell in acquisition of hypoxic-ischemic tolerance in the immoture rat"Am J Obstet Gynecol. 182・2. 380-386 (2000)

Tomoaki Ikeda,MD,Tsuyoma Ikenoue,MD,Xiao Y.Xia,MD,and Yix.Xia,MD：“内皮细胞中 72-kd 热休克蛋白表达在未成熟大鼠获得缺氧缺血耐受性中的重要作用“Am J Obstet Gynecol. 182・2. 380-386 (2000)