IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3β?
IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3β?
复制标题
DOI：
10.1111/j.1460-9568.2005.03982.x
复制
发表时间：
2005-03-01
影响因子：
3.4
通讯作者：
Hagberg, H
中科院分区：
文献类型：
--
作者：
Brywe, KG;Mallard, C;Hagberg, H
胰岛素样生长因子 I (IGF-I) 是一种促进神经元生长、分化和存活的神经营养因子。 IGF-I 的神经保护作用先前已在成年和幼年大鼠脑损伤模型中得到证实。我们想要研究IGF-I对7日龄新生大鼠缺氧缺血（HI）后的神经保护作用以及IGF-I在体内的作用机制。我们还想研究 HI 和/或 IGF-I 对磷脂酰肌醇 3 激酶 (PI3K) 途径中丝氨酸/苏氨酸激酶 Akt 和糖原合成酶激酶 3 beta (GSK3 beta) 的影响。 HI 后，同侧的磷酸化 Akt (pAkt) 和磷酸化 GSK3 beta (pGSK3 beta) 免疫反应性立即丧失，而对侧半球的免疫反应性降低。 45 分钟后，pAkt 水平恢复至对照值，而 HI 后 4 小时 pGSK3 beta 仍保持较低水平。与媒介物处理的动物相比，HI后给予IGF-I（50μg静脉注射）导致脑损伤（微管相关蛋白的损失）减少40%。没有 HI 的 IGF-I 处理显示出 pAkt 增加，而胞质中的 pGSK3 β 减少，但核部分增加。与媒介物处理的大鼠相比，HI后IGF-I处理增加了同侧半球胞质溶胶中的pAkt以及胞质溶胶和核部分中的pGSK3β，同时伴随着caspase-3和caspase-9样活性的降低。总之，IGF-I 在 HI 恢复期间诱导 Akt 激活，与 GSK3 β 失活相结合，可以解释半胱天冬酶激活减弱和未成熟大脑损伤减少。
Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3 beta (GSK3 beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3 beta (pGSK3 beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3 beta remained low 4 h after HI. Administration of IGF-I (50 mu g i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3 beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3 beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3 beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.