Pre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage

Eur J Pharmacol. 2015 Sep 5;762:293-8. doi: 10.1016/j.ejphar.2015.05.059. Epub 2015 Jun 6.

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).

Keywords: Angiotensin; Brain; Natriuretic peptide; Neprilysin; Stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aminobutyrates / administration & dosage
  • Aminobutyrates / pharmacology*
  • Angiotensin II / blood
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / pharmacology*
  • Animals
  • Atrial Natriuretic Factor / blood
  • Brain / blood supply
  • Brain / drug effects
  • Brain / metabolism
  • Cerebrovascular Circulation / drug effects
  • Drug Combinations
  • Infarction, Middle Cerebral Artery / blood
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / physiopathology
  • Infarction, Middle Cerebral Artery / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neprilysin / antagonists & inhibitors*
  • Oxidative Stress / drug effects
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / pharmacology*
  • Renin / blood
  • Sodium / blood
  • Tetrazoles / administration & dosage
  • Tetrazoles / pharmacology*
  • Water / metabolism

Substances

  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Drug Combinations
  • Protease Inhibitors
  • Tetrazoles
  • Water
  • Angiotensin II
  • Atrial Natriuretic Factor
  • Sodium
  • Renin
  • Neprilysin
  • sacubitril-valsartan