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 language | English |
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Article number | e005198 |
Journal | Journal of the American Heart Association |
Volume | 6 |
Issue number | 5 |
DOIs | |
State | Published - 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