Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model
Blockade of BDNF signalling attenuates chronic visceral hypersensitivity in an IBS-like rat model
复制标题
DOI：
10.1002/ejp.1534
复制
发表时间：
2020-02-05
影响因子：
3.6
通讯作者：
Lin, Chun
中科院分区：
文献类型：
--
作者：
Fan, Fei;Tang, Ying;Lin, Chun
肠易激综合征（IBS）是一种常见的功能性疾病，以慢性腹痛和排便改变为特征。肠易激综合征患者内脏过敏的有效治疗仍然具有挑战性。本研究探讨脑源性神经营养因子（BDNF）和酪氨酸激酶受体B （TrkB）的作用，以及ANA-12 （TrkB的选择性拮抗剂）对ibs样大鼠慢性内脏超敏反应的影响。方法采用新生儿母分离法（NMS）建立ibs样大鼠模型，采用腹外斜肌肌电图（EMG）对结肠直肠膨胀（CRD）的反应评估内脏超敏反应。通过鞘内注射不同剂量的ANA-12，研究ANA-12对内脏超敏反应的影响，并通过开场试验确定ANA-12对运动是否有副作用。测定胸腰椎BDNF、TrkB受体和蛋白激酶M zeta （PKM zeta）的表达，探讨其在慢性内脏超敏反应中的作用。对第二层胸腰椎浅背角（SDH）神经元进行全细胞记录。结果BDNF和TrkB在NMS动物胸腰段脊髓中表达增强。ANA-12对NMS大鼠的内脏超敏反应无副作用。ANA-12处理后PKM zeta表达明显降低。NMS大鼠胸腰段第二层SDH神经元自发性兴奋性突触后电流（sEPSCs）频率增加。ANA-12灌注后，NMS大鼠sEPSCs的振幅和频率降低。结论新生儿母分离通过激活成年大鼠胸腰段脊髓BDNF-TrkB-PKM zeta信号引起内脏超敏反应和突触活性增加。PKM zeta能够增强NMS大鼠AMPA受体（AMPAR）介导的sEPSCs。ANA-12通过阻断BDNF/TrkB信号传导，减轻了NMS大鼠的内脏超敏反应和突触活性。在NMS大鼠中，ANA-12通过BDNF-TrkB-PKM zeta信号通路减弱内脏超敏反应，并通过ampar降低突触活性。这表明ANA-12可能是一种有趣的治疗慢性内脏过敏的新药物。
Background Irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and changes in bowel movements. Effective therapy for visceral hypersensitivity in IBS patients remains challenging. This study investigated the roles of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) and the effect of ANA-12 (a selective antagonist of TrkB) on chronic visceral hypersensitivity in an IBS-like rat model.Methods An IBS-like rat model was established through neonatal maternal separation (NMS), and visceral hypersensitivity was assessed by electromyographic (EMG) responses of the abdominal external oblique muscles to colorectal distention (CRD). Different doses of ANA-12 were injected intrathecally to investigate the effect of that drug on visceral hypersensitivity, and the open field test was performed to determine whether ANA-12 had side effects on movement. Thoracolumbar spinal BDNF, TrkB receptor and Protein kinase M zeta (PKM zeta) expression were measured to investigate their roles in chronic visceral hypersensitivity. Whole-cell recordings were made from thoracolumbar superficial dorsal horn (SDH) neurons of lamina II.Results The expression of BDNF and TrkB was enhanced in the thoracolumbar spinal cord of the NMS animals. ANA-12 attenuated visceral hypersensitivity without side effects on motricity in NMS rats. PKM zeta expression significantly decreased after the administration of ANA-12. The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased in the thoracolumbar SDH neurons of lamina II in NMS rats. The amplitude and frequency of sEPSCs were reduced after perfusion with ANA-12 in NMS rats.Conclusions Neonatal maternal separation caused visceral hypersensitivity and increased synaptic activity by activating BDNF-TrkB-PKM zeta signalling in the thoracolumbar spinal cord of adult rats. PKM zeta was able to potentiate AMPA receptor (AMPAR)-mediated sEPSCs in NMS rats. ANA-12 attenuated visceral hypersensitivity and synaptic activity by blocking BDNF/TrkB signalling in NMS rats.Significance ANA-12 attenuates visceral hypersensitivity via BDNF-TrkB-PKM zeta signalling and reduces synaptic activity through AMPARs in NMS rats. This knowledge suggests that ANA-12 could represent an interesting novel therapeutic medicine for chronic visceral hypersensitivity.