Nature Medicine9, 1180 - 1186 (2003)
Published online: 24 August 2003; | doi:10.1038/nm911
A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia
Tiziana Borsello1, Peter G H Clarke1, Lorenz Hirt4, Alessandro Vercelli2, Mariaelena Repici2, Daniel F Schorderet3, Julien Bogousslavsky4
& Christophe Bonny3
1
Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Rue du Bugnon 9, CH-1005, Switzerland.
2
Department of Anatomy, Pharmacology and Forensic Medicine, Corso M.D'Azeglio 52, 10126 Torino, Italy.
3
Division of Medical Genetics, CHUV-University Hospital, CH-1011 Lausanne, Switzerland.
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.
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