| Co-Investigator(Kenkyū-buntansha) |
SHIMOYA Koichiro Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40291950)
KANAGAWA Takeshi Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (40346218)
FUKUDA Hirotsugu National Cardiovascular Center, Doctor, 産科, 医師 (40324751)
KIMURA Tadashi Osaka University, Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (90240845)
早田 憲司 大阪大学, 医学系研究科, 助手 (80314433)
古山 将康 大阪大学, 医学系研究科, 助教授 (00183351)
神崎 徹 大阪大学, 医学系研究科, 助教授 (00263278)
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| Budget Amount *help |
¥46,410,000 (Direct Cost: ¥35,700,000、Indirect Cost: ¥10,710,000)
Fiscal Year 2005: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Fiscal Year 2004: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
Fiscal Year 2003: ¥22,620,000 (Direct Cost: ¥17,400,000、Indirect Cost: ¥5,220,000)
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| Research Abstract |
Inflammation is an important factor for hypoxia-ischemia (HI) brain injury. Interleukin (IL)-18 is a proinflammatory cytokine which may be a contributor to injury in the immature brain after HI. To investigate the effects of post-HI hypothermia on IL-18 in the developing brain, 7-day-old rats were subjected to left carotid artery ligation followed by 8% oxygen for 60 min and divided into a hypothermia group (rectal temperature 32 degrees C for 24 h) and a normothermia group (36 degrees C for 24 h). The significant increase of the IL-18 mRNA was observed in the ipsilateral hemispheres of the normothermia group at 24 h and 72 h after HI compared with controls, but the level in the ipsilateral hemispheres of the hypothermia group was significantly reduced at both time points, compared with the normothermia group, respectively. The IL-18 protein level in the ipsilateral hemispheres of the normothermia group significantly increased at 72 h after HI compared with controls, however, the prote
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in level of the hypothermia group was significantly decreased, compared with the normothermia group. IL-18-positive cells were observed throughout the entire cortex, corpus callosum (CC) and striatum in the ipsilateral hemispheres of normothermia group at 72 h after HI, however, little positive cells were observed in the hypothermia group. Double labeling immunostaining found that most of the IL-18-positive cells were colocalized with lectin, which is a marker of microglia. The number of ameboid microglia (AM) in the normothermia group was significantly increased in cortex and CC, compared with the number in controls, but there were very few ramified microglia (RM) in these areas. In contrast, the number of AM in the hypothermia group was significantly decreased in cortex and CC, compared with the number in the normothermia group, and there were no significant differences in the number of AM and RM between the hypothermia group and controls. In conclusion, we found that IL-18 mRNA and the protein level were attenuated by post-HI hypothermia and that post-HI hypothermia may decrease microglia activation in the developing brain.
This study was undertaken to investigate the long-term effect of hypercapnia on neonatal hypoxic-ischemic brain injury, we tested its effect in a neonatal rat hypoxia-ischemia model. The rats were subjected to unilateral carotid artery ligation and exposure to 8% oxygen for 30 minutes. Six percent carbon dioxide was administered to the neonatal rats during unilateral hypoxia-ischemia, and the motor function and neurologic outcomes were determined 3 months later. Significant motor functional improvement was observed in the hypercapnic animals, as judged by the Montoya staircase test. The unilateral brain injury was significantly ameliorated in the hypercapnic animals, and this amelioration was well correlated with the motor functional performance. Cerebral blood flow during hypoxia-ischemia, monitored by laser Doppler flowmetry, was better preserved in the hypercapnic animals. Our results suggest that mild hypercapnia during hypoxia-ischemia may provide long-lasting motor functional as well as neurologic protection for immature brains, possibly by increasing cerebral blood flow during hypoxia.
Hypothermia is a potential therapy for cerebral hypoxic ischemic injury of not only adults but also neonates. However, the side effects of hypothermia in the developing brain, where a massive amount of neurogenesis occurs, remain unclear. We investigated the proliferation of neural progenitor cells by systemic application of the thymidine analog 5-bromodeoxyuridine (BrdU) in neonatal rats in a severe hypothermic environment. The rat pups were divided into two groups, a hypothermia group (30 degrees C) and a normothermia group (37 degrees C). After the pups were placed for 21 h in each environment, BrdU was injected intraperitoneally to label dividing cells, and then the pups were sacrificed at 24 h. We examined the number of BrdU-labeled cells in the subventricular zone of the periventricle and the subgranular zone of the dentate gyrus. In the hypothermic environment, BrdU-labeled cells significantly decreased in number in the dentate gyrus, but not in the periventricular region. Thus, the severe hypothermic environment induced a decrease of neurogenesis in the neonatal rat. These observations are noteworthy regarding clinical hypothermia therapy following cerebral hypoxic ischemic injury during the perinatal period. Less
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