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

This peptide inhibitor shows promise in reducing brain lesions in animal models of ischemia, but its applicability to human stroke treatment is not established.

Summary and findings

This study evaluated the neuroprotective effects of a cell-penetrating peptide inhibitor of c-Jun N-terminal kinase (JNK) in models of cerebral ischemia. In adult mice, intraventricular administration reduced lesion volume by more than 90% for at least 14 days. In 14-day-old rat pups, systemic delivery resulted in lesion reductions of 78% and 49% at 6 and 12 hours post-ischemia, respectively.

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.

Limitations

Not reported in abstract.

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