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

Nat Med. 2003 Sep;9(9):1180-6. doi: 10.1038/nm911. Epub 2003 Aug 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Behavior, Animal / drug effects
  • Brain Ischemia / pathology
  • Brain Ischemia / prevention & control*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology*
  • Excitatory Amino Acid Agonists / adverse effects
  • Gene Products, tat / genetics
  • Gene Products, tat / metabolism
  • Genes, fos / drug effects
  • In Vitro Techniques
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / pathology
  • JNK Mitogen-Activated Protein Kinases
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • N-Methylaspartate / adverse effects
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology
  • Peptides / pharmacology*
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Gene Products, tat
  • Mapk8ip protein, mouse
  • Mapk8ip1 protein, rat
  • Neuroprotective Agents
  • Peptides
  • Recombinant Proteins
  • N-Methylaspartate
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases