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Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia.

Abstract
Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1 beta, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.
AuthorsYlva Carlsson, Anna-Lena Leverin, Maj Hedtjärn, Xiaoyang Wang, Carina Mallard, Henrik Hagberg
JournalDevelopmental neuroscience (Dev Neurosci) Vol. 31 Issue 5 Pg. 420-6 ( 2009) ISSN: 1421-9859 [Electronic] Switzerland
PMID19672071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright(c) 2009 S. Karger AG, Basel.
Chemical References
  • Carbazoles
  • 3,9-bis((ethylthio)methyl)-K-252a
  • Caspase 3
Topics
  • Animals
  • Animals, Newborn
  • Apoptosis (drug effects)
  • Blotting, Western
  • Brain (drug effects, metabolism, pathology)
  • Carbazoles (pharmacology)
  • Caspase 3 (metabolism)
  • Cell Count
  • Enzyme-Linked Immunosorbent Assay
  • Hypoxia-Ischemia, Brain (drug therapy, metabolism)
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Inflammation (metabolism)
  • Microglia (drug effects, metabolism)
  • Neurons (drug effects, metabolism)
  • Organ Size (drug effects)
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction (drug effects)
  • Statistics, Nonparametric

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