title: Inhibition of Let7c microRNA is neuroprotective in a rat intracerebral hemorrhage model.
abstract: Intracerebral hemorrhage (ICH) is a devastating neurological disease with a grave prognosis. We evaluated microRNA (miRNA) expression after ICH and evaluated Let7c as a therapeutic target. We harvested hemorrhagic brain 24 hours after collagenase induced ICH in the rat. Microarray analysis was performed to compare the miRNAs expression pattern between hemorrhagic hemisphere and contralateral hemisphere. An in vitro thrombin toxicity model and blood injection ICH model were also used to evaluate miRNA expression. We selected miRNA for the therapeutic target study after reviewing target gene databases and their expression. The antagonistic sequence of the selected miRNA (antagomir) was used to evaluate its therapeutic potential in the in vitro thrombin toxicity and in vivo ICH models. Among 1,088 miRNAs analyzed, let7c was induced in the thrombin and ICH models. Let7c antagomir treatment increased cell survival in the in vitro thrombin injury model and improved neurological function at 4 weeks after ICH. Let7c antagomir decreased perihematoma edema, apoptotic cell death and inflammation around hematoma. Let7c antagomir also induced insulin like growth factor receptor 1 (IGF1R) protein and phosphorylated serine threonine kinase after ICH. This study shows a distinct miRNA expression pattern after ICH. The let7c antagomir reduced cell death and edema and enhanced neurological recovery at least in part by activating the IGF1R pro-survival pathway. This suggests blocking let7c might be a potential therapeutic target in ICH.
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Chung-Ang University Medical Center, Seoul, South Korea.
authors: Jeong-Min
authors: JM
authors: Kim
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Soon-Tae
authors: ST
authors: Lee
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Kon
authors: K
authors: Chu
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Keun-Hwa
authors: KH
authors: Jung
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors: Jin Hee
authors: JH
authors: Kim
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors: Jung-Suk
authors: JS
authors: Yu
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors: Soyun
authors: S
authors: Kim
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors: So Hee
authors: SH
authors: Kim
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors: Dong-Kyu
authors: DK
authors: Park
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Jangsup
authors: J
authors: Moon
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
authors: Jaejun
authors: J
authors: Ban
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Manho
authors: M
authors: Kim
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Sang Kun
authors: SK
authors: Lee
authors: Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.
authors: Jae-Kyu
authors: JK
authors: Roh
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D017364:Collagenases / Q000009:adverse effects; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006490:Hemostatics / Q000633:toxicity*; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013917:Thrombin / Q000633:toxicity*; D015854:Up-Regulation
chemical_list: D006490:Hemostatics; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D009841:Oligonucleotides; D017526:Receptor, IGF Type 1; D013917:Thrombin; D017364:Collagenases