Inhibition of the JNK/AP-1 pathway reduces neuronal death and improves behavioral outcome after neonatal hypoxic-ischemic brain injury
Inhibition of the JNK/AP-1 pathway reduces neuronal death and improves behavioral outcome after neonatal hypoxic-ischemic brain injury
复制标题
DOI：
10.1016/j.bbi.2009.09.008
复制
发表时间：
2010-07-01
影响因子：
15.1
通讯作者：
Kavelaars, Annemieke
中科院分区：
文献类型：
--
作者：
Nijboer, Cora H.;van der Kooij, Michael A.;Kavelaars, Annemieke
围产期缺氧缺血性脑损伤一直是一个重要的临床问题。我们研究了MAP激酶c-Jun n -末端激酶（JNK）在新生儿HI脑损伤中的作用。JNK调节一些转录（通过AP-1激活）和非转录过程参与脑损伤，如炎症和细胞死亡/存活。P7大鼠单侧颈动脉闭塞和缺氧致HI。hi诱导的脑AP-1激活在hi后3-6 h达到峰值。HI后立即腹腔注射jnk抑制剂TAT-JBD可阻止AP-1的激活。在HI后3小时内使用TAT-JBD治疗可使早期神经元损伤减少30%。JNK/AP-1抑制未降低hi诱导的细胞因子/趋化因子表达。凋亡细胞死亡指标分析显示，TAT-JBD可显著降低hi诱导的活性caspase 3的升高。然而，凋亡的上游介质：活性caspase 8，裂解Bid，线粒体]细胞色素c释放和caspase 9裂解在TAT-JBD后没有减少。TAT-JBD抑制了hi诱导的Smac/DIABLO的增加，这是一种阻止caspase 3激活的IAPs抑制剂。TAT-JBD治疗还减少了α -fodrin的裂解，表明calpain介导的脑损伤减轻。TAT-JBD治疗的神经保护作用是持久的，在hi后14周，灰质和白质损伤减少了50%，同时感觉运动行为和认知功能显着改善。总之，通过TAT-JBD治疗JNK抑制新生儿HI脑损伤，治疗窗口期为3小时，并能持久改善解剖和行为。我们认为TAT-JBD抑制线粒体Smac/DIABLO释放和calpain激活有助于神经保护。(C) 2009爱思唯尔公司版权所有。
Perinatal hypoxic-ischemic (HI) brain damage continues to be a major clinical problem. We investigated the contribution of the MAP kinase c-Jun N-terminal kinase (JNK), to neonatal HI brain damage. JNK regulates several transcriptional (via AP-1 activation) and non-transcriptional processes involved in brain damage such as inflammation and cell death/survival.P7 rats were subjected to HI by unilateral carotid artery occlusion and hypoxia. HI-induced activation of cerebral AP-1 peaked at 3-6 h post-HI. Intraperitoneal administration of the JNK-inhibitor TAT-JBD immediately after HI prevented AP-1 activation. TAT-JBD treatment within 3 h after HI reduced early neuronal damage by similar to 30%. JNK/AP-1 inhibition did not reduce HI-induced cytokine/chemokine expression. Analysis of indicators of apoptotic cell death revealed that TAT-JBD markedly reduced the HI-induced increase in active caspase 3. However, the upstream mediators of apoptosis: active caspase 8, cleaved Bid, mitochondria] cytochrome c release and caspase 9 cleavage were not reduced after TAT-JBD. TAT-JBD inhibited the HI-induced increase in Smac/DIABLO, an inhibitor of IAPs that prevent activation of caspase 3. TAT-JBD treatment also reduced cleavage of alpha-fodrin, indicating that calpain-mediated brain damage was reduced. Neuroprotection by TAT-JBD treatment was long-lasting as gray- and white matter damage was diminished by similar to 50% at 14 weeks post-HI concomitantly with marked improvement of sensorimotor behavior and cognitive functioning.In conclusion, JNK inhibition by TAT-JBD treatment reduced neonatal HI brain damage with a therapeutic window of 3 h and long-lasting anatomical and behavioral improvements. We propose that inhibition of mitochondrial Smac/DIABLO release and calpain activation contribute to neuroprotection by TAT-JBD. (C) 2009 Elsevier Inc. All rights reserved.