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

Tiziana Borsello, Peter G H Clarkel, Lorenz Hirt, Alessandro Vercelli, Mariaelena Repici, Daniel F. Schorderet, Julien Bogousslavsky, Christophe Bonny

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1180-1186
Number of pages7
JournalNature Medicine
Volume9
Issue number9
DOIs
Publication statusPublished - Sep 1 2003

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia'. Together they form a unique fingerprint.

  • Cite this

    Borsello, T., Clarkel, P. G. H., Hirt, L., Vercelli, A., Repici, M., Schorderet, D. F., Bogousslavsky, J., & Bonny, C. (2003). A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Medicine, 9(9), 1180-1186. https://doi.org/10.1038/nm911