Abstract

Peptides targeting the mitogen-activated protein kinase pathway (JNK/Jun) fail to reduce infarct volume after permanent MCAO in Sprague Dawley rats

Author(s): Cindy Si, Kym Campbell, Jane L. Cross, Paul M. Watt, Nadia Milech, Neville W. Knuckey and Bruno P. Meloni

In this study we have assessed the ability of two TAT-fused peptides PYC36D-TAT and JNKI-1D-TAT (JNKI-1 or XG-102), which respectively inhibit jun proto-oncogene (c-Jun) and c-Jun N-terminal kinase (JNK) activation, to reduce infarct volume and improve functional outcome (adhesive tape removal) following permanent focal cerebral ischemia/pMCAO in Sprague Dawley rats. In addition, PYC36L-TAT fused to an ischemic brain homing peptide (HP-PYC36L-TAT) was also assessed. Prior to animal experiments all PYC36D-TAT, JNKI-1D-TAT and HP-PYC36L-TAT peptide batches were tested in vitro and protected cortical neurons against glutamate excitotoxicity. Rats were treated intravenously in two separate trials. Trial 1 used high peptide doses (PYC36D-TAT: 500, 1000 or 1500 nmol/kg; JNKI-1D-TAT: 500, 1000 or 1500 nmol/kg; PYC36Dscrambled-TAT: 1120 nmol/kg) administered 1 hour after MCAO. Trial 2 used lower doses (PYC36D-TAT: 50 or 250 nmol/kg; HP-PYC36L-TAT: 250 nmol/kg; JNKI-1D-TAT: 250 nmol/kg; D-TAT: 250 nmol/kg) administered 2 hours after MCAO. Contrary to other stroke animal studies, but in line with our previous findings, no treatment significantly reduced infarct volume or improved functional score measurements compared to vehicle (saline) treated animals when assessed 24 hours post-MCAO.