1. 2018;21;E633-E642Recurrent Headache Increases Blood-Brain Barrier Permeability and VEGF Expression in Rats
   Experimental Trial
   Xiujuan Mi, PhD, Li Ran, MD, Lixue Chen, PhD, and Guangcheng Qin, MD.

BACKGROUND: The blood-brain barrier (BBB) is an important anatomical structure of the central nervous system (CNS) that limits the penetration of a variety of substances from the blood into the parenchyma. Dysfunction of the BBB is involved in various CNS disorders, including stroke, inflammation, and pain. However, the evidence concerning its role in migraine is insufficient.

OBJECTIVE: This study will investigate whether recurrent headache increases BBB permeability and vascular endothelial growth factor (VEGF) expression in a rat model.

STUDY DESIGN: This study used an experimental design.

SETTING: The research took place in the Laboratory Research Center at The First Affiliated Hospital of Chongqing Medical University.

METHODS: Eighty male Sprague-Dawley rats were randomly divided into 3 groups: inflammatory soup (IS), control (PBS), and treatment (IS+Sumatriptan) groups. Recurrent headache was induced by episodic IS stimulation: 20 µL of IS were pumped into the dura 3 times per week in rats. The control group was administered 20 µL of PBS. The rats in the treatment group were simultaneously treated with sumatriptan (300 ug/kg, intraperitoneal) at the same time that IS was applied to the dura. Mechanical nociceptive thresholds were examined by electronic von Frey filaments with rigid tips. BBB permeability changes were measured with Evans blue (EB). The expression of VEGF was measured by double labeling and Western blotting.

RESULTS: After 4 IS applications, the mechanical nociceptive thresholds significantly decreased. In addition, the mechanical hypersensitivity persisted for 4 hours after 9 applications. Only after 9 applications did the BBB permeability increase, as demonstrated by the EB tracer. The BBB disruption was accompanied by an elevation in VEGF expression. Sumatriptan treatment significantly reduced the mechanical hypersensitivity induced by IS stimulations and decreased the BBB disruption and VEGF expression.

LIMITATIONS: Potential mechanisms that underlie the relationship between BBB and VEGF were not examined in this study.

CONCLUSIONS: The present study showed that repeated IS stimulations induced long-lasting allodynia, increased BBB permeability, and upregulated VEGF expression, all of which could be attenuated by early sumatriptan treatment.

KEY WORDS: Migraine, inflammatory soup, blood-brain barrier, vascular endothelial growth factor, sumatriptan