title: Pre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage.
abstract: Angiotensin II receptor blockers (ARBs) are known to prevent ischemic brain damage after stroke. Natriuretic peptides, which are increased by a neprilysin inhibitor, are also reported to protect against brain damage. Therefore, we investigated the possible protective effect of valsartan (VAL) compared with LCZ696 (VAL+ neprilysin inhibitor; 1:1) after middle cerebral artery (MCA) occlusion. Eight-week-old male C57BL/6J mice were treated with VAL (3mg/kg per day) or LCZ696 (6mg/kg per day) for 2 weeks before MCA occlusion. Blood pressure and heart rate were measured by telemetry. Cerebral blood flow (CBF) was determined by laser-Doppler flowmetry. Ischemic area was evaluated by triphenytetrasodium chloride staining, and oxidative stress was determined by dihydroethidium staining. Blood pressure and heart rate were not significantly different before and after treatment. Pre-treatment with LCZ696 or VAL reduced the ischemic area, and this effect of LCZ696 was more marked than that of VAL pre-treatment. The decrease in CBF in the peripheral region of the ischemic area was significantly attenuated by pre-treatment with LCZ696 or VAL, without any significant effect on CBF in the core region. VAL or LCZ696 pre-treatment significantly decreased the increase of superoxide anion production in the cortex on the ischemic side. However, no significant difference in CBF and superoxide anion production was observed between VAL and LCZ696 pre-treatment. The preventive effect of LCZ696 on ischemic brain damage after stroke was more marked than that of VAL. LCZ696 could be used as a new approach to prevent brain damage after stroke. (246 words).
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Bai
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan. Electronic address: mmogi@m.ehime-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakaoka
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Kan-No
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Tsukuda
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan; Department of Pediatrics, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Chisaka
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan; Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kukida
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Bao-Shuai
authors.initials: BS
authors.lastname: Shan
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan; Department of Pediatrics, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan; Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Higaki
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Iwanami
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Tohon, Ehime 791-0295, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000284:Administration, Oral; D000613:Aminobutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001713:Biphenyl Compounds; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004338:Drug Combinations; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D012964:Sodium / Q000097:blood; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000068756:Valsartan; D014867:Water / Q000378:metabolism
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D013777:Tetrazoles; D014867:Water; D000804:Angiotensin II; D000068756:Valsartan; D009320:Atrial Natriuretic Factor; D012964:Sodium; D012083:Renin; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Angiotensin; Brain; Natriuretic peptide; Neprilysin; Stroke