A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia

被引:589
作者
Borsello, T
Clarke, PGH
Hirt, L
Vercelli, A
Repici, M
Schorderet, DF
Bogousslavsky, J
Bonny, C
机构
[1] Univ Lausanne, Inst Biol Cellulaire & Morphol, CH-1005 Lausanne, Switzerland
[2] Dept Anat Pharmacol & Forens Med, I-10126 Turin, Italy
[3] CHU Vaudois, Univ Hosp, Div Med Genet, CH-1011 Lausanne, Switzerland
[4] CHU Vaudois, Univ Hosp, Lab Rech Neurol, CH-1011 Lausanne, Switzerland
关键词
D O I
10.1038/nm911
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Neuronal death in cerebral ischemia is largely due to excitotoxic mechanisms, which are known to activate the c-Jun N-terminal kinase (JNK) pathway. We have evaluated the neuroprotective power of a cell-penetrating, protease-resistant peptide that blocks the access of JNK to many of its targets. We obtained strong protection in two models of middle cerebral artery occlusion (MCAO): transient occlusion in adult mice and permanent occlusion in 14-d-old rat pups. In the first model, intraventricular administration as late as 6 h after occlusion reduced the lesion volume by more than 90% for at least 14 d and prevented behavioral consequences. In the second model, systemic delivery reduced the lesion by 78% and 49% at 6 and 12 h after ischemia, respectively. Protection correlated with prevention of an increase in c-Jun activation and c-Fos transcription. In view of its potency and long therapeutic window, this protease-resistant peptide is a promising neuroprotective agent for stroke.
引用
收藏
页码:1180 / 1186
页数:7
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