Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia.
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.
Carlsson
Ylva
Y
Department of Obstetrics and Gynecology, Perinatal Center, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Leverin
Anna-Lena
AL
Hedtjärn
Maj
M
Wang
Xiaoyang
X
Mallard
Carina
C
Hagberg
Henrik
H
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002227:Carbazoles / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D004797:Enzyme-Linked Immunosorbent Assay; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric
D002227:Carbazoles; C106592:3,9-bis((ethylthio)methyl)-K-252a; D053148:Caspase 3