短时间低温与同时抑制Src 激酶对新生猪脑缺氧缺血后 Ca2+/钙调蛋白激酶 IV 活性和神经病理学的影响。
Effect of Concurrent Src Kinase Inhibition with Short-Duration Hypothermia on Ca2+/Calmodulin Kinase IV Activity and Neuropathology after Hypoxia-Ischemia in the Newborn Swine Brain.
机构信息
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Children's National Medical Center, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
出版信息
Neonatology. 2018;113(1):37-43. doi: 10.1159/000480067. Epub 2017 Oct 13.
BACKGROUND
Hypoxia-ischemia (HI) results in increased activation of Ca2+/calmodulin kinase IV (CaM kinase IV) mediated by Src kinase. Therapeutic hypothermia ameliorates neuronal injury in the newborn.
HYPOTHESIS
Inhibition of Src kinase concurrently with hypothermia further attenuates the hypoxia-induced increased activation of CaM kinase IV compared with hypothermia alone.
DESIGN/METHODS: Ventilated piglets were exposed to HI, received saline or a selective Src kinase inhibitor (PP2), and were cooled to 33°C. Neuropathology, adenosine triphosphate (ATP) and phosphocreatine (PCr) concentrations, and CaM kinase IV activity were determined.
RESULTS
The neuropathology mean score (mean ± SD) was 0.4 ± 0.43 in normoxia-normothermia (p < 0.05 vs. hypoxia-normothermia), 3.5 ± 0.89 in hypoxia-normothermia (p < 0.05 vs. normoxia-normothermia), 0.7 ± 0.73 in hypoxia-hypothermia (p < 0.05 vs. normoxia-normothermia), and 0.5 ± 0.70 in normoxia-hypothermia (p < 0.05 vs. hypoxia-normothermia). The CaM kinase IV activity in cerebral tissue (pmol Pi/mg protein/min; mean ± SD) was 2,002 ± 729 in normoxia-normothermia, 1,704 ± 18 in normoxia-hypothermia, 6,017 ± 2,510 in hypoxia-normothermia, 4,104 ± 542 in hypoxia-hypothermia (p < 0.05 vs. normoxia-hypothermia), and 2,165 ± 415 in hypoxia-hypothermia with PP2 (p < 0.05 vs. hypoxia-hypothermia). The hypoxic groups with and without hypothermia or Src kinase inhibitor were comparable in the levels of ATP and PCr, indicating that they were similar in their degree of energy failure prior to treatments. Hypothermia or Src kinase inhibitor (PP2) did not restore the ATP and PCr levels.
CONCLUSIONS
Hypothermia and Src kinase inhibition attenuated apoptotic cell death and improved neuropathology after hypoxia. The combination of short-duration hypothermia with Src kinase inhibition following hypoxia further attenuates the increased activation of CaM kinase IV compared to hypothermia alone in the newborn swine brain.
背景
缺氧缺血（HI）导致Src 激酶介导的 Ca2+/钙调蛋白激酶 IV（CaM 激酶 IV）的激活增加。治疗性低温可改善新生儿的神经元损伤。
假说
与单独低温相比，同时抑制 Src 激酶和低温可进一步减轻缺氧诱导的 CaM 激酶 IV 活性增加。
设计/方法：对通气小猪进行 HI 暴露，接受生理盐水或选择性 Src 激酶抑制剂（PP2），并冷却至 33°C。测定神经病理学、三磷酸腺苷（ATP）和磷酸肌酸（PCr）浓度以及 CaM 激酶 IV 活性。
结果
常氧正常体温组的神经病理学平均评分（均值 ± SD）为 0.4 ± 0.43（与缺氧正常体温组相比，p < 0.05），缺氧正常体温组为 3.5 ± 0.89（与常氧正常体温组相比，p < 0.05），缺氧低温组为 0.7 ± 0.73（与常氧正常体温组相比，p < 0.05），常氧低温组为 0.5 ± 0.70（与缺氧正常体温组相比，p < 0.05）。脑组织 CaM 激酶 IV 活性（pmol Pi/mg 蛋白/min；均值 ± SD）分别为常氧正常体温组 2002 ± 729，常氧低温组 1704 ± 18，缺氧正常体温组 6017 ± 2510，缺氧低温组 4104 ± 542（与常氧低温组相比，p < 0.05），缺氧低温组加 PP2 组 2165 ± 415（与缺氧低温组相比，p < 0.05）。缺氧组无论是否接受低温或 Src 激酶抑制剂治疗，其 ATP 和 PCr 水平均相似，表明在治疗前其能量衰竭程度相似。低温或 Src 激酶抑制剂（PP2）均不能恢复 ATP 和 PCr 水平。
结论
低温和 Src 激酶抑制可减轻缺氧后细胞凋亡性死亡并改善神经病理学。与单独低温相比，短暂低温与缺氧后 Src 激酶抑制相结合可进一步减轻新生猪脑 CaM 激酶 IV 的激活增加。
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