Molecular Neurobiology

, Volume 53, Issue 7, pp 4529–4538 | Cite as

Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice

  • Lei Liu
  • Masashi Fujimoto
  • Fumihiro Kawakita
  • Fumi Nakano
  • Kyoko Imanaka-Yoshida
  • Toshimichi Yoshida
  • Hidenori Suzuki
Article

Abstract

The role of vascular endothelial growth factor (VEGF) in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The aim of this study was to investigate effects of anti-VEGF therapy on EBI after SAH. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or two dosages (0.2 and 1 μg) of anti-VEGF antibody were randomly administrated by an intracerebroventricular injection. Neuroscore, brain water content, immunoglobulin G staining, and Western blotting were performed to evaluate EBI at 24–48 h. To confirm the role of VEGF, anti-VEGF receptor (VEGFR)-2 (a major receptor of VEGF) antibody was intracerebroventricularly administered and the effects on EBI were evaluated at 24 h. A higher dose, but not a lower dose, of anti-VEGF antibody significantly ameliorated post-SAH neurological impairments and brain edema at 24–48 h post-SAH. Post-SAH blood-brain barrier disruption was also inhibited by anti-VEGF antibody. The protective effects of anti-VEGF antibody were associated with the inhibition of post-SAH induction of VEGF, VEGFR-2, phosphorylated VEGFR-2, interleukin-1β and a matricellular protein tenascin-C (TNC). Anti-VEGFR-2 antibody also suppressed post-SAH neurological impairments and brain edema associated with VEGFR-2 inactivation and TNC downregulation. These findings demonstrated that VEGF causes post-SAH EBI via VEGFR-2 and TNC and that anti-VEGF therapy is effective for post-SAH EBI.

Keywords

Subarachnoid hemorrhage Vascular endothelial growth factor Blood-brain barrier Tenascin-C Antibody neutralization 

Abbreviations

ANOVA

Analysis of variance

BBB

Blood-brain barrier

CSF

Cerebrospinal fluid

EBI

Early brain injury

EGF

Epidermal growth factor

IL

Interleukin

MAPK

Mitogen-activation protein kinase

PBS

Phosphate-buffered saline

PDGF

Platelet-derived growth factor

p-VEGFR-2

Phosphorylated vascular endothelial growth factor receptor-2

SAH

Subarachnoid hemorrhage

TNC

Tenascin-C

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

ZO

Zona occludens

Supplementary material

12035_2015_9386_MOESM1_ESM.pdf (5.2 mb)
ESM 1(PDF 5366 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lei Liu
    • 1
  • Masashi Fujimoto
    • 1
  • Fumihiro Kawakita
    • 1
  • Fumi Nakano
    • 1
  • Kyoko Imanaka-Yoshida
    • 2
    • 3
  • Toshimichi Yoshida
    • 2
    • 3
  • Hidenori Suzuki
    • 1
    • 3
  1. 1.Department of NeurosurgeryMie University Graduate School of MedicineTsuJapan
  2. 2.Department of Pathology and Matrix BiologyMie University Graduate School of MedicineTsuJapan
  3. 3.Research Center for Matrix BiologyMie University Graduate School of MedicineTsuJapan

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