Long lasting neuroprotection by JNK activity blockade in severe cerebral ischemia

The c-Jun-N-terminal kinase (JNK) plays a key role in ischemia-induced neuronal death. The peptide D-JNKI1, obtained by linking the 20-amino-acid JNK-binding motif of JIP-1/IB1 (JBD20) to the 10-amino-acid HIV Tat (48-57) transporter sequence, binds to JNK and inhibits its activity. We have previously demonstrated that the D-JNKI1 administration six hours after ischemia inhibits JNK activity and decreases ischemic lesion size. Here we studied how long DJNKI1 remains active and maintains its neuroprotective effect in cerebral ischemia. Young P14 Sprague Dawley rats underwent permanent middle cerebral artery coagulation followed by transient clamping of the common carotid artery at different time intervals after D-JNKI1 administration (2 to 5 days, 1 and 2 weeks). Analysis of lesion size by the Neurolucida software showed that D-JNKI1 administration up to 4 days before ischemia reduced significantly the infarct volumes by 45.77%. Therefore D-JNKI1 administration is effective in preventing cell death for several days in severe cerebral ischemia