5-Lipoxygenase inhibition reduces inflammation and neuronal apoptosis via AKT signaling after subarachnoid hemorrhage in rats

Aging (Albany NY). 2021 Apr 20;13(8):11752-11761. doi: 10.18632/aging.202869. Epub 2021 Apr 20.

Abstract

Early brain injury (EBI) is a major contributor to the high mortality and morbidity after subarachnoid hemorrhage (SAH). Inflammatory responses and neuronal apoptosis are important causes of EBI. Because 5- lipoxygenase (5-LOX) is known to be involved various central nervous system diseases, we investigated the effects of 5-LOX inhibition during EBI after SAH. Zileuton and LY294002 were used to inhibit expression of 5-LOX and Akt, respectively. We found that 5-LOX expression was significantly increased in the cytoplasm of cortical neurons after SAH and was accompanied by upregulated expression of the inflammatory factors LTB4, TNF-α, IL-1β and IL-6; upregulation of the pro-apoptotic factor Bax; downregulation of the anti-apoptotic factor Bcl-2; and an increased apoptosis rate. Gastric Zileuton administration significantly suppressed all of those effects and improved neurological function. Zileuton also upregulated activated (phosphorylated) AKT levels, and these beneficial effects of Zileuton were abolished by intracerebroventricular infusion of the PI3K inhibitor LY294002. Taken together, these findings indicate that 5-LOX mediates pro-inflammatory and pro-apoptotic effects that contribute to EBI after SAH and that those effects are suppressed by activation of PI3K/Akt signaling. This suggests targeting 5-LOX may be an effective approach to treating EBI after SAH.

Keywords: 5-LOX; apoptosis; early brain injury; inflammation; subarachnoid hemorrhage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Apoptosis / drug effects
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Brain Injuries / drug therapy*
  • Brain Injuries / immunology
  • Brain Injuries / pathology
  • Chromones / administration & dosage
  • Disease Models, Animal
  • Humans
  • Hydroxyurea / administration & dosage
  • Hydroxyurea / analogs & derivatives
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / pathology
  • Infusions, Intraventricular
  • Lipoxygenase Inhibitors / administration & dosage*
  • Male
  • Morpholines / administration & dosage
  • Neurons / drug effects*
  • Neurons / immunology
  • Neurons / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors / administration & dosage
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Subarachnoid Hemorrhage / complications
  • Subarachnoid Hemorrhage / drug therapy*
  • Subarachnoid Hemorrhage / immunology
  • Subarachnoid Hemorrhage / pathology

Substances

  • Chromones
  • Lipoxygenase Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Arachidonate 5-Lipoxygenase
  • Akt1 protein, rat
  • Proto-Oncogene Proteins c-akt
  • zileuton
  • Hydroxyurea