Hypoxic-ischemic tolerance in newborn rat brain

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儿童残疾的主要原因之一。我们发现，7日龄大鼠的亚致死缺氧或低温预处理降低了随后缺氧缺血性应激引起的脑损伤的严重程度。我们将这种现象命名为“缺氧-化学耐受性”（Ota等）。中华妇产科杂志1998；[j] .武汉大学学报：自然科学版。SGI Journal; 2000；102 - 5)。在高温预处理后6、12和24小时观察到高低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，与缺氧缺血耐受性的关系最为密切。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，“缺氧缺血耐受性”似乎与未成熟脑内皮功能改变有关。作为另一种内源性保护机制，我们开始研究神经营养因子的作用。采用酶联免疫吸附法测定正常发育大鼠从出生至出生后第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大鼠出生后1 ~ 21天脑内神经胶质细胞系源性神经营养因子（GDNF）的表达。脑实质注射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。

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.