A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia.
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.
Borsello
Tiziana
T
Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Rue du Bugnon 9, CH-1005, Switzerland. Tiziana.Borsello@ibcm.unil.ch
Clarke
Peter G H
PG
Hirt
Lorenz
L
Vercelli
Alessandro
A
Repici
Mariaelena
M
Schorderet
Daniel F
DF
Bogousslavsky
Julien
J
Bonny
Christophe
C
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D016762:Genes, fos / Q000187:drug effects; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D016202:N-Methylaspartate / Q000009:adverse effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D015696:Gene Products, tat; C490665:Mapk8ip protein, mouse; C110528:Mapk8ip1 protein, rat; D018696:Neuroprotective Agents; D010455:Peptides; D011994:Recombinant Proteins; D016202:N-Methylaspartate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases