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

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

Research output: Contribution to journalArticlepeer-review

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
Early online date24 Aug 2003
DOIs
Publication statusPublished - 1 Sep 2003

Bibliographical note

Funding: This work was supported by grants 31-50598.97, 32-54119.98, 31-61736.00, 32-65139.01 and 3200-68306.02 from the Swiss National Science Foundation, the San Paolo Bank (Italy) and the Alzheimer Project (Italian Ministry of Health). We are particularly grateful to P. Nicod and the Botnar Foundation for human and financial support.

Keywords

  • Adaptor Proteins
  • Mice
  • Brain Ischemia
  • Enzyme Inhibitors
  • Drug effects
  • JNK Mitogen-Activated Protein Kinases
  • Inbred ICR
  • Neurons
  • Rats

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