School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China.
Institute of Meterial Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China.
J Headache Pain. 2022 Jan 3;23(1):1. doi: 10.1186/s10194-021-01374-9.
Chronic migraine places a disabling burden on patients, which is extensively modeled by the nitroglycerin (NTG)-treated animal model. Although the NF-κB pathway is involved in an increase in CGRP levels and activation of the trigeminal system in the NTG model, the relationship between NTG and neuroinflammation remains unclear. This study aimed to optimize a chronic NTG rat model with hyperalgesia and the ethological capacity for estimating migraine therapies and to further explore the underlying mechanism of NTG-induced migraine.
Rats were administered different doses of NTG s.c. daily or every 2 d; 30 min and 2 h later, the mechanical threshold was tested. After 9 d, the rats were injected with EB or Cy5.5 for the permeability assay. The other animals were sacrificed, and then, brainstem and caudal trigeminal ganglion were removed to test CGRP, c-Fos and NOS activity; Cytokines levels in the tissue and serum were measured by ELISA; and NF-κB pathway and blood-brain barrier (BBB)-related indicators were analyzed using western blotting. Immunohistochemistry was performed to observe microglial polarization and IL-17A T cell migration in the medulla oblongata.
NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition, resulting in progressive hyperalgesia and migraine behavior. TNC neuroinflammation with increases in cytokines, CGRP and c-Fos and activation of the NF-κB pathway was observed, and these changes were alleviated by ibuprofen. Furthermore, NTG administration increased BBB permeability by altering the levels functional proteins (RAGE, LRP1, AQP4 and MFSD2A) and structural proteins (ZO-1, Occludin and VE-cadherin-2) to increase peripheral IL-17A permeation into the medulla oblongata, activating microglia and neuroinflammation, and eventually causing hyperalgesia and migraine attack.
This study confirmed that NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition to provoke migraine, resulting in mechanical hyperalgesia and observable migraine-like behavior. Furthermore, IL-17A crossed the blood-brain barrier into the medulla oblongata, triggering TNC activation through microglia-mediated neuroinflammation. This process was a novel mechanism in NTG-induced chronic migraine, suggesting that IL-17A might be a novel target in the treatment of migraine.
慢性偏头痛给患者带来了致残负担，这在硝化甘油（NTG）治疗动物模型中得到了广泛的模拟。尽管 NF-κB 通路参与了 CGRP 水平的增加和三叉神经系统的激活，但 NTG 与神经炎症之间的关系仍不清楚。本研究旨在优化一种具有痛觉过敏和评估偏头痛治疗方法的行为能力的慢性 NTG 大鼠模型，并进一步探讨 NTG 诱导偏头痛的潜在机制。
大鼠每天或每两天皮下给予不同剂量的 NTG；30 分钟和 2 小时后，测试机械阈值。9 天后，用 EB 或 Cy5.5 进行通透性测定。然后处死其他动物，取出脑干和尾状三叉神经节，检测 CGRP、c-Fos 和 NOS 活性；通过 ELISA 测定组织和血清中的细胞因子水平；采用 Western blot 分析 NF-κB 通路和血脑屏障（BBB）相关指标。免疫组织化学观察延髓中小胶质细胞极化和 IL-17A T 细胞迁移。
NTG（10mg/kg，皮下，每两天一次，共 5 次注射）是最佳条件，导致进行性痛觉过敏和偏头痛行为。观察到 TNC 神经炎症伴有细胞因子、CGRP 和 c-Fos 的增加以及 NF-κB 通路的激活，这些变化可被布洛芬缓解。此外，NTG 给药通过改变功能蛋白（RAGE、LRP1、AQP4 和 MFSD2A）和结构蛋白（ZO-1、Occludin 和 VE-cadherin-2）的水平来增加 BBB 通透性，增加外周 IL-17A 渗透到延髓，激活小胶质细胞和神经炎症，最终导致痛觉过敏和偏头痛发作。
本研究证实，NTG（10mg/kg，皮下，每两天一次，共 5 次注射）是引发偏头痛的最佳条件，导致机械性痛觉过敏和可观察到的偏头痛样行为。此外，IL-17A 通过血脑屏障进入延髓，通过小胶质细胞介导的神经炎症触发 TNC 激活。这一过程是 NTG 诱导慢性偏头痛的一种新机制，提示 IL-17A 可能是偏头痛治疗的一个新靶点。
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