Netrin-1 preserves blood-brain barrier integrity through deleted in colorectal cancer/focal adhesion kinase/RhoA signaling pathway following subarachnoid hemorrhage in rats

Zongyi Xie, Budbazar Enkhjargal, Cesar Reis, Lei Huang, Weifeng Wan, Jiping Tang, Yuan Cheng, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Background- Netrin-1 (NTN-1) has been established to be a novel intrinsic regulator of blood-brain barrier (BBB) maintenance. This study was carried out to investigate the potential roles of exogenous NTN-1 in preserving BBB integrity after experimental subarachnoid hemorrhage (SAH) as well as the underlying mechanisms of its protective effects. Methods and Results- A total of 309 male Sprague-Dawley rats were subjected to an endovascular perforation model of SAH. Recombinant NTN-1 was administered intravenously 1 hour after SAH induction. NTN-1 small interfering RNA or Deleted in Colorectal Cancer small interfering RNA was administered intracerebroventricular at 48 hours before SAH. Focal adhesion kinase inhibitor was administered by intraperitoneal injection at 1 hour prior to SAH. Neurological scores, brain water content, BBB permeability, RhoA activity, Western blot, and immunofluorescence staining were evaluated. The expression of endogenous NTN-1 and its receptor Deleted in Colorectal Cancer were increased after SAH. Administration of exogenous NTN-1 significantly reduced brain water content and BBB permeability and ameliorated neurological deficits at 24 and 72 hours after SAH. Exogenous NTN-1 treatment significantly promoted phosphorylated focal adhesion kinase activation and inhibited RhoA activity, as well as upregulated the expression of ZO-1 and Occludin. Conversely, depletion of endogenous NTN-1 aggravated BBB breakdown and neurological impairments at 24 hours after SAH. The protective effects of NTN-1 at 24 hours after SAH were also abolished by pretreatment with Deleted in Colorectal Cancer small interfering RNA and focal adhesion kinase inhibitor. Conclusions- NTN-1 treatment preserved BBB integrity and improved neurological functions through a Deleted in Colorectal Cancer/focal adhesion kinase/RhoA signaling pathway after SAH. Thus, NTN-1 may serve as a promising treatment to alleviate early brain injury following SAH.

Original languageEnglish
Article numbere005198
JournalJournal of the American Heart Association
Volume6
Issue number5
DOIs
StatePublished - May 5 2017

ASJC Scopus Subject Areas

  • Cardiology and Cardiovascular Medicine

Keywords

  • Blood-brain barrier
  • Brain edema
  • Early brain injury
  • Netrin-1
  • Subarachnoid hemorrhage
  • Occludin/biosynthesis
  • Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors
  • Injections, Intravenous
  • rho GTP-Binding Proteins/biosynthesis
  • Colorectal Neoplasms/complications
  • Gene Expression Regulation, Neoplastic
  • Male
  • Brain/drug effects
  • Netrin-1/administration & dosage
  • Subarachnoid Hemorrhage/etiology
  • Neoplasms, Experimental
  • Recombinant Proteins/administration & dosage
  • Signal Transduction
  • Injections, Intraperitoneal
  • Zonula Occludens-1 Protein/biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Blotting, Western
  • Animals
  • Blood-Brain Barrier/drug effects
  • Infusions, Intraventricular
  • RNA, Neoplasm/genetics

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