Article: article from journal or magazin.
A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia.
In Vitro Journal Article Research Support, Non-U.S. Gov't --- Old month value: Sep
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.
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, 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
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