Limited role of the c-Jun N-terminal kinase pathway in a neonatal rat model of cerebral hypoxia-ischemia.
D-JNKI1, a cell-permeable peptide inhibitor of the c-Jun N-terminal kinase (JNK) pathway, has been shown to be a powerful neuroprotective agent after focal cerebral ischemia in adult mice and young rats. We have investigated the potential neuroprotective effect of D-JNKI1 and the involvement of the JNK pathway in a neonatal rat model of cerebral hypoxia-ischemia (HI). Seven-day-old rats underwent a permanent ligation of the right common carotid artery followed by 2 h of hypoxia (8% oxygen). Treatment with D-JNKI1 (0.3 mg/kg intraperitoneally) significantly reduced early calpain activation, late caspase 3 activation and, in the thalamus, autophagosome formation, indicating an involvement of JNK in different types of cell death: necrotic, apoptotic, and autophagic. However, the size of the lesion was unchanged. Further analysis showed that neonatal HI induced an immediate decrease in JNK phosphorylation (reflecting mainly JNK1 phosphorylation) followed by a slow progressive increase (including JNK3 phosphorylation 54 kDa), whereas c-jun and c-fos expression were both strongly activated immediately after HI. In conclusion, unlike in adult ischemic models, JNK is only moderately activated after severe cerebral HI in neonatal rats and the observed positive effects of D-JNKI1 are insufficient to give neuroprotection. Thus, for perinatal asphyxia, D-JNKI1 can only be considered in association with other therapies.
Ginet
Vanessa
V
Division of Neonatology, Department of Pediatrics and Pediatric Surgery, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
Puyal
Julien
J
Magnin
Guylène
G
Clarke
Peter G H
PG
Truttmann
Anita C
AC
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001237:Asphyxia / Q000503:physiopathology; D001343:Autophagy; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D016762:Genes, fos / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases; D002154:Calpain; D053148:Caspase 3; C478085:D-JNKI-1