title: LOX-1 is a novel therapeutic target in neonatal hypoxic-ischemic encephalopathy.
abstract: Neonatal hypoxic-ischemic encephalopathy (HIE) remains a serious burden in neonatal care. Hypothermia provides a good outcome in some babies with HIE. Here, we investigated the biological mechanisms of its neuroprotective effect and sought for a new therapeutic target. We made neonatal HIE rats and subjected some of them to hypothermia at 28°C for 3 hours. We pathologically confirmed the efficacy of hypothermia against the neonatal HIE brain. To clarify the molecular mechanism of hypothermia's efficacy, we analyzed mRNA expression, immunoassay, and pathology in the brain with or without HIE and/or hypothermia. We selected from these analyses 12 molecules with possible neuroprotective effects. After identification of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) as a therapeutic target candidate, we examined the efficacy of an anti-LOX-1 neutralizing antibody in neonatal HIE rats. Administration of an anti-LOX-1 neutralizing antibody reduced infarction area, brain edema, and apoptotic cell death to a degree comparable with hypothermia. Protection from those pathological conditions was considered part of the therapeutic mechanism of hypothermia. The efficacy of administering anti-LOX-1 neutralizing antibody was similar to that of hypothermia. LOX-1 is a promising therapeutic target in neonatal HIE, and the inhibition of LOX-1 may become a novel treatment for babies who have experienced asphyxia.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Akamatsu
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuguchi
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. Electronic address: itoh@ncnp.go.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007036:Hypothermia, Induced; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E