title: Inotropic support against early brain injury improves cerebral hypoperfusion and outcomes in a murine model of subarachnoid hemorrhage.
abstract: Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2.5h after SAH induction or concomitant intravenous dobutamine infusion (15μg/kg/min) with or without HIF inhibitor 2-methoxyestradiol (2ME2) (10mg/kg) administered intraperitoneally. Neurobehavioral function was assessed daily by neurological scores and open field testing. DCI was defined 3days later by detecting a new infarction on MRI. Global CBF depression was notable early after SAH, but dobutamine showed significant improvement in CBF, lower incidence of DCI, and better recovery of neuroscores and open field test variables compared with isoflurane postconditioning (P<0.05). CBF over the entire brain on day 1 predicted DCI with a cut-off of 36.5ml/100g/min (80% specificity and 67% sensitivity), with a better area under the curve (0.83 versus 0.75) than the hemispheric CBF measured on the perforated side. The dobutamine-mediated outcomes were attenuated (P<0.05) by 2ME2 pretreatment. The data suggest that cardiac support with dobutamine improves global CBF depression induced by early brain injury, leading to reduced prevalence of DCI and better functional outcomes after experimental SAH, in which HIF may be acting as a critical mediator.
authors.affiliation: Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan; Graduate School of Psychology, Kobe Shoin Women's University, Kobe, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Mutoh
authors.affiliation: Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan; Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan. Electronic address: tmutoh@tiara.ocn.ne.jp.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Mutoh
authors.affiliation: Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan; Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Preclinical Evaluation, IDAC, Tohoku University, Sendai, Japan.
authors.forename: Kazumasu
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Tatewaki
authors.affiliation: Research Institute for Brain and Blood Vessels-AKITA, Akita, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Taki
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004280:Dobutamine / Q000008:administration & dosage*; D051793:Hypoxia-Inducible Factor 1 / Q000008:administration & dosage; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D013345:Subarachnoid Hemorrhage / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D002316:Cardiotonic Agents; D051793:Hypoxia-Inducible Factor 1; D018696:Neuroprotective Agents; D004280:Dobutamine
keywords: Cerebral blood flow; Delayed cerebral ischemia; Dobutamine; Early brain injury; Subarachnoid hemorrhage