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.
|Titolo:||A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia|
|Parole Chiave:||tissue-plasminogen activator; therapeutic window; induced apoptosis; injury; stroke; brain; JNK; neurons; nucleus; damage|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore BIO/16 - Anatomia Umana
|Data di pubblicazione:||2003|
|Digital Object Identifier (DOI):||10.1038/nm911|
|Appare nelle tipologie:||01 - Articolo su periodico|