title: NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death.
abstract: Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed protein kinase, which regulates cell fate in numerous injury conditions. Therefore, ASK1 may be a promising novel therapeutic target for injury. However, the expression and distribution of ASK1 in the perinatal brain following hypoxia-ischemia (HI) remains to be elucidated. In the present study, western blotting and immunofluorescence were used to determine the expression and distribution of ASK1 and any associated downstream targets in the perinatal rat brain following HI. NQDI‑1, a specific inhibitor of ASK1 was intracerebroventricularly injected following neonatal rats brain insult for neuroprotection. The results revealed an increased expression of ASK1 and this expression was localized to the neurons and astrocytes, compared with the sham controls. Additionally, it was demonstrated that the ASK1/ c‑Jun N‑terminal kinases (JNK) pathway was involved in the brain damage following HI in neonatal rats. Notably, NQDI‑1 significantly inhibited the in vivo expression levels of ASK1, phosphorylated (p‑)JNK, p‑c‑Jun, p53 and caspase 3. Reduced acute hypoxic‑ischemic cerebral injury and cell apoptosis was observed following the injection of NQDI‑1. Collectively, NQDI-1 attenuated acute perinatal hypoxic‑ischemic cerebral injury by inhibiting the expression of ASK1 and cell apoptosis. This may be a promising novel neuroprotective inhibitor for perinatal cerebra injury.
authors.affiliation: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China.
authors.forename: Hu
authors.initials: H
authors.lastname: Hao
authors.affiliation: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China.
authors.forename: Sitao
authors.initials: S
authors.lastname: Li
authors.affiliation: Central Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630 P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China.
authors.forename: Bingqing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Pediatrics, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001060:Aporphines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000592751:2,7-dioxo-2,7-dihydro-3H-naphtho(1,2,3-de)quinoline-1-carboxylate; D001060:Aporphines; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D053148:Caspase 3