Cohen Cinder Faith, Prudente Arthur Silveira, Berta Temugin, Lee Sang Hoon
Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, United States.
Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Front Mol Neurosci. 2021 Nov 1;14:765181. doi: 10.3389/fnmol.2021.765181. eCollection 2021.
Migraine is a common neurological disorder with few available treatment options. Recently, we have demonstrated the role of transient receptor potential cation channel subfamily C member 4 (TRPC4) in itch and the modulation of the calcitonin gene-related peptide (CGRP), a biomarker and emerging therapeutic target for migraine. In this study, we characterized the role of TRPC4 in pain and evaluated its inhibition as anti-migraine pain therapy in preclinical mouse models. First, we found that TRPC4 is highly expressed in trigeminal ganglia and its activation not only mediates itch but also pain. Second, we demonstrated that the small-molecule inhibitor ML204, a specific TRPC4 antagonist, significantly reduced episodic and chronic migraine-like behaviors in male and female mice after injection of nitroglycerin (NTG), a well-known migraine inducer in rodents and humans. Third, we found a significant decrease in CGRP protein levels in the plasma of both male and female mice treated with ML-204, which largely prevented the development of chronic migraine-like behavior. Using sensory neuron cultures, we confirmed that activation of TRPC4 elicited release of CGRP, which was significantly diminished by ML-204. Collectively, our findings identify TRPC4 in peripheral sensory neurons as a mediator of CGRP release and NTG-evoked migraine. Since a TRPC4 antagonist is already in clinical trials, we expect that this study will rapidly lead to novel and effective clinical treatments for migraineurs.
偏头痛是一种常见的神经系统疾病，可用的治疗方法很少。最近，我们已经证明瞬时受体电位阳离子通道亚家族C成员4（TRPC4）在瘙痒以及降钙素基因相关肽（CGRP）的调节中所起的作用，CGRP是偏头痛的一种生物标志物和新兴治疗靶点。在本研究中，我们对TRPC4在疼痛中的作用进行了表征，并在临床前小鼠模型中评估了其作为抗偏头痛疼痛疗法的抑制作用。首先，我们发现TRPC在三叉神经节中高表达，其激活不仅介导瘙痒，还介导疼痛。其次，我们证明小分子抑制剂ML204（一种特异性TRPC4拮抗剂）在注射硝酸甘油（NTG，一种在啮齿动物和人类中广为人知的偏头痛诱发剂）后能显著减少雄性和雌性小鼠的发作性和慢性偏头痛样行为。第三，我们发现用ML-204处理的雄性和雌性小鼠血浆中CGRP蛋白水平显著降低，这在很大程度上阻止了慢性偏头痛样行为的发展。使用感觉神经元培养物，我们证实TRPC4的激活引发CGRP的释放，而ML-204可显著减少这种释放。总体而言，我们的研究结果确定外周感觉神经元中的TRPC4是CGRP释放和NTG诱发偏头痛的介质。由于一种TRPC4拮抗剂已在进行临床试验，我们预计这项研究将迅速为偏头痛患者带来新的有效临床治疗方法。
