Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02129, USA.
J Neurosci. 2012 Jun 13;32(24):8112-5. doi: 10.1523/JNEUROSCI.0219-12.2012.
The stress-activated protein kinase c-Jun N-terminal kinase (JNK) is a central regulator in neuronal death cascades. In animal models of cerebral ischemia, acute inhibition of JNK reduces infarction and improves outcomes. Recently however, emerging data suggest that many neuronal death mediators may have biphasic properties-deleterious in the acute stage but potentially beneficial in the delayed stage. Here, we hypothesized that JNK may also have biphasic actions, so some caution may be required in the development of JNK inhibitors for stroke. Sprague Dawley rats underwent 90 min transient occlusions of the middle cerebral artery. Acute treatment (10 min poststroke) with the JNK inhibitor SP600125 reduced infarction volumes. In contrast, delayed treatment (7 d poststroke) worsened infarction volumes and neurological outcomes. Immunostaining of peri-infarct cortex showed that JNK inhibition suppressed surrogate markers of neurovascular remodeling, including matrix metalloproteinase-9 in GFAP-positive astrocytes and microvascular density. Consistent with these in vivo data, SP600125 significantly suppressed in vitro angiogenesis in rat brain endothelial cultures. Our data provide initial proof-of-concept that the neuronal death target JNK may also participate in endogenous processes of neurovascular remodeling and recovery after cerebral ischemia.
应激激活蛋白激酶 c-Jun N-末端激酶（JNK）是神经元死亡级联反应的中央调节因子。在脑缺血动物模型中，JNK 的急性抑制可减少梗死并改善预后。然而，最近出现的证据表明，许多神经元死亡介质可能具有双相特性——在急性阶段有害，但在延迟阶段可能有益。在这里，我们假设 JNK 也可能具有双相作用，因此在开发用于中风的 JNK 抑制剂时需要谨慎。Sprague Dawley 大鼠接受 90 分钟的大脑中动脉短暂闭塞。JNK 抑制剂 SP600125 的急性治疗（中风后 10 分钟）可减少梗死体积。相比之下，延迟治疗（中风后 7 天）会加重梗死体积和神经功能结局。梗塞周围皮质的免疫染色显示，JNK 抑制抑制了神经血管重塑的替代标志物，包括 GFAP 阳性星形胶质细胞中的基质金属蛋白酶-9 和微血管密度。与这些体内数据一致，SP600125 显著抑制了大鼠脑内皮细胞培养物中的体外血管生成。我们的数据初步证明了神经元死亡靶点 JNK 也可能参与脑缺血后神经血管重塑和恢复的内源性过程。
