Calcitonin gene-related peptide receptor antagonist BIBN4096BS regulates synaptic transmission in the vestibular nucleus and improves vestibular function via PKC/ERK/CREB pathway in an experimental chronic migraine rat model

作者全名："Tian, Ruimin; Zhang, Yun; Pan, Qi; Wang, Yunfeng; Wen, Qianwen; Fan, Xiaoping; Qin, Guangcheng; Zhang, Dunke; Chen, Lixue; Zhang, Yixin; Zhou, Jiying"

作者地址："[Tian, Ruimin; Zhang, Yun; Pan, Qi; Wang, Yunfeng; Fan, Xiaoping; Zhang, Yixin; Zhou, Jiying] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, 1st You Yi Rd, Chongqing 400016, Peoples R China; [Wang, Yunfeng] Nanchong Cent Hosp, Dept Neurol, Nanchong, Peoples R China; [Wen, Qianwen; Qin, Guangcheng; Zhang, Dunke; Chen, Lixue] Chongqing Med Univ, Affiliated Hosp 1, Lab Res Ctr, Chongqing, Peoples R China"

通信作者："Zhang, YX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, 1st You Yi Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF HEADACHE AND PAIN

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000766165400001

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：23

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：CGRP; Migraine; Vestibular dysfunction; Vestibular nucleus; Central sensitization; Synaptic transmission

摘要："Background Vestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN). Methods A CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining. Results The expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM. Conclusions The present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM."

基金机构：National Natural Science Foundation of China [82101296]; Cultivation Fund of The First Affiliated Hospital of Chongqing Medical University [ZYRC2020-01]

基金资助正文：This study was supported by the National Natural Science Foundation of China (No: 82101296 to Yixin Zhang) and the Cultivation Fund of The First Affiliated Hospital of Chongqing Medical University (NO: ZYRC2020-01 to Yixin Zhang).