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

作者：Liu Lei; Fujimoto Masashi; Kawakita Fumihiro; Nakano Fumi; Imanaka Yoshida Kyoko; Yoshida Toshimichi; Suzuki Hidenori^*

来源：Molecular Neurobiology, 2016, 53(7): 4529-4538.

DOI：10.1007/s12035-015-9386-9

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

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 mu g) 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-1 beta 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.

• 出版日期2016-9