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Nat Med. 2003 Sep;9(9):1180-6. Epub 2003 Aug 24.

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

Author information

1
Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Rue du Bugnon 9, CH-1005, Switzerland. Tiziana.Borsello@ibcm.unil.ch

Abstract

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.

PMID:
12937412
DOI:
10.1038/nm911
[Indexed for MEDLINE]

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