Centre for Neuroscience, Xi'an Jiaotong-Liverpool University, Suzhou, China.
Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, 111 Renái Road, Suzhou, 215123, People's Republic of China.
J Headache Pain. 2019 Mar 6;20(1):25. doi: 10.1186/s10194-019-0978-z.
The transient receptor potential ankyrin A 1 (TRPA1) channel and calcitonin gene-related peptide (CGRP) are targets for migraine prophylaxis. This study aimed to understand their mechanisms in migraine by investigating the role of TRPA1 in cortical spreading depression (CSD) in vivo and exploring how reactive oxygen species (ROS)/TRPA1/CGRP interplay in regulating cortical susceptibility to CSD.
Immunohistochemistry was used for detecting TRPA1 expression. CSD was induced by K on the cerebral cortex, monitored using electrophysiology in rats, and intrinsic optical imaging in mouse brain slices, respectively. Drugs were perfused into contralateral ventricle of rats. Lipid peroxidation (malondialdehyde, MDA) analysis was used for indicating ROS level.
TRPA1 was expressed in cortical neurons and astrocytes of rats and mice. TRPA1 deactivation by an anti-TRPA1 antibody reduced cortical susceptibility to CSD in rats and decreased ipsilateral MDA level induced by CSD. In mouse brain slices, HO facilitated submaximal CSD induction, which disappeared by the antioxidant, tempol and the TRPA1 antagonist, A-967079; Consistently, TRPA1 activation reversed prolonged CSD latency and reduced magnitude by the antioxidant. Further, blockade of CGRP prolonged CSD latency, which was reversed by HO and the TRPA1 agonist, allyl-isothiocyanate, respectively.
ROS/TRPA1/CGRP signaling plays a critical role in regulating cortical susceptibility to CSD. Inhibition ROS and deactivation of TRPA1 channels may have therapeutic benefits in preventing stress-triggered migraine via CGRP.
瞬时受体电位锚蛋白 1（TRPA1）通道和降钙素基因相关肽（CGRP）是偏头痛预防的靶点。本研究旨在通过研究 TRPA1 在体内皮质扩散性抑制（CSD）中的作用，以及探索活性氧（ROS）/TRPA1/CGRP 相互作用如何调节皮质对 CSD 的易感性，来了解它们在偏头痛中的机制。
使用免疫组织化学检测 TRPA1 的表达。CSD 通过 K 在大脑皮层上诱导，分别在大鼠中用电生理学监测，在小鼠脑片上用内源性光学成像监测。药物灌注到大鼠的对侧脑室。脂质过氧化（丙二醛，MDA）分析用于指示 ROS 水平。
TRPA1 在大鼠和小鼠的皮质神经元和星形胶质细胞中表达。TRPA1 失活通过抗 TRPA1 抗体降低了大鼠皮质对 CSD 的易感性，并降低了 CSD 诱导的同侧 MDA 水平。在小鼠脑片中，HO 促进了亚最大 CSD 的诱导，而抗氧化剂 tempol 和 TRPA1 拮抗剂 A-967079 使其消失；一致地，TRPA1 激活逆转了抗氧化剂延长的 CSD 潜伏期和降低的幅度。此外，CGRP 的阻断延长了 CSD 潜伏期，HO 和 TRPA1 激动剂丙烯基异硫氰酸酯分别逆转了这一现象。
ROS/TRPA1/CGRP 信号在调节皮质对 CSD 的易感性方面起着关键作用。抑制 ROS 和 TRPA1 通道失活可能通过 CGRP 在预防应激触发的偏头痛方面具有治疗益处。
