Lack of neuroprotection of inhibitory peptides targeting Jun/JNK after transient focal cerebral ischemia in spontaneously hypertensive rats.

Abstract

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) after transient focal cerebral ischemia in Spontaneously Hypertensive (SH) rats. PYC36D-TAT and JNKI-1D-TAT peptide batches used for experiments were tested in vitro and protected cortical neurons against glutamate excitotoxicity. Rats were treated intravenously with three different doses of PYC36D-TAT (7.7, 76, or 255 nmol/kg), JNKI-1D-TAT (255 nmol/kg), D-TAT peptide (255 nmol/kg), or saline (vehicle control), 10 minutes after reperfusion after 90 minutes of middle cerebral artery occlusion (MCAO). Contrary to other stroke models, no treatment significantly reduced infarct volume or improved functional score measurements compared with vehicle-treated animals when assessed 48 hours after MCAO. Additionally, assessment of the JNKI-1D-TAT peptide, when administered 1 or 2 hours after reperfusion after 90 minutes of MCAO, also did not improve histological or functional outcomes at 48 hours after occlusion. This study is the first to evaluate the efficacy of PYC36D-TAT and JNKI-1D-TAT using the SH rat, which has recently been shown to be more sensitive to AMPA receptor activation rather than to NMDA receptor activation after cerebral ischemia, and which may have contributed to the negative findings.

• Authors: William R Gow, Kym Campbell, Amanda J Meade, Paul M Watt, Nadia Milech, Neville W Knuckey, Bruno P Meloni
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 31 Issue 12 Pg. e1-8 (Dec 2011) ISSN: 1559-7016 [Electronic] United States
• PMID: 21971350 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuropeptides
• Neuroprotective Agents
• Oncogene Protein p65(gag-jun)
• Peptides
• Carbon Dioxide
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 8
• D-JNKI-1
• Oxygen

Topics

• Animals
• Blood Pressure (physiology)
• Carbon Dioxide (blood)
• Dose-Response Relationship, Drug
• Infarction, Middle Cerebral Artery (pathology)
• Ischemic Attack, Transient (drug therapy, pathology)
• JNK Mitogen-Activated Protein Kinases (drug effects)
• Laser-Doppler Flowmetry
• Male
• Mitogen-Activated Protein Kinase 8 (genetics)
• Neuropeptides (pharmacology)
• Neuroprotective Agents
• Oncogene Protein p65(gag-jun) (drug effects)
• Oxygen (blood)
• Peptides (pharmacology)
• Psychomotor Performance (physiology)
• Rats
• Rats, Inbred SHR