Elucidating Novel Therapeutic Targets for Oropharyngeal Dysphagia: Focusing on TRPA1 and TRPV4 Channels

本研究旨在探讨TRPA 1和TRPV 4在吞咽反射中的作用。我们观察了TRPA 1和TRPV 4在吞咽相关区域的传入神经元上的表达。TRPA 1主要定位于小到中等直径的神经元，TRPV 4主要定位于大到中等直径的神经元。我们还观察到，局部应用TRPA 1的化学激动剂，异硫氰酸烯丙酯（AITC）或TRPV 4的激动剂，GSK 1016790 A，在吞咽相关区域剂量依赖性地促进吞咽反射的触发。先前局部应用TRPA 1或TRPV 4拮抗剂分别显著降低AITC或GSK 1016790 A诱导的吞咽反射。冷AITC（4 °C）的应用非常短暂地将现场温度降低到<17 °C（TRPA 1可以被激活的温度），但对反射的触发没有影响。相比之下，通过持续流动冷AITC或通过应用冰AITC将现场温度降低至<17 °C持续更长时间，反而延迟/阻止了AITC诱导的反射的触发。先前应用TRPA 1拮抗剂对点状机械刺激诱导反射的阈值或低力或高力连续机械压力刺激诱导反射的数量没有影响。我们已经在《科学报告》和《前沿》上发表了这些数据。Cell. Neurosci.“期刊。目前我们正在研究TRPV 4在水诱导吞咽反射中的作用。

In this project we investigate the involvement of TRPA1 and TRPV4 in swallowing reflex. We observed TRPA1 and TRPV4 expression on afferent neurons of the swallowing-related regions. TRPA1 localized majorly on small to medium diameter neurons and TRPV4 majorly localized on large to medium diameter neurons. We also observed that topical application of a chemical agonist for TRPA1, allyl isothiocyanate (AITC) or agonist for TRPV4, GSK1016790A, in the swallowing-related regions dose-dependently facilitated the triggering of swallowing reflex. Prior topical application of antagonists for TRPA1 or TRPV4 significantly reduced the AITC or GSK1016790A-induced swallowing reflex, respectively. Application of cold AITC (4 °C) very briefly reduced the on-site temperature to <17 °C (temperature at which TRPA1s can be activated), but had no effect on triggering of the reflex. By contrast, reducing the on-site temperature to <17 °C for a longer time by continuous flow of cold AITC or by application of iced AITC paradoxically delayed/prevented the triggering of AITC-induced reflexes. Prior application of the TRPA1 antagonist had no effect on the threshold for the punctate mechanical stimuli-induced reflex or the number of low-force or high-force continuous mechanical pressure stimuli-induced reflexes. We have published these data in "Scientific Reports" and "Front. Cell. Neurosci." journals. Now we are conducting research on the involvement of TRPV4 in water-induced swallowing reflex.