Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice.
Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice.
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DOI：
10.3389/fnmol.2021.765181
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发表时间：
2021
影响因子：
4.8
通讯作者：
Lee SH
中科院分区：
文献类型：
--
作者：
Cohen CF;Prudente AS;Berta T;Lee SH
偏头痛是一种常见的神经系统疾病，几乎没有可用的治疗方案。最近，我们已经证明了瞬时受体电位阳离子通道亚家族C成员4（TRPC 4）在瘙痒和降钙素基因相关肽（CGRP），偏头痛的生物标志物和新兴的治疗靶点的调制中的作用。在这项研究中，我们表征了TRPC 4在疼痛中的作用，并在临床前小鼠模型中评估了其作为抗偏头痛治疗的抑制作用。首先，我们发现TRPC 4在三叉神经节中高度表达，并且其激活不仅介导瘙痒，还介导疼痛。第二，我们证明了小分子抑制剂ML 204，一种特异性TRPC 4拮抗剂，在注射硝酸甘油（NTG）（一种众所周知的啮齿动物和人类偏头痛诱导剂）后，显著减少了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治疗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TRPC 4的激活引起CGRP的释放，其被ML-204显著减少。总的来说，我们的研究结果确定TRPC 4在外周感觉神经元作为CGRP释放和NTG诱发的偏头痛的介质。由于TRPC 4拮抗剂已经在临床试验中，我们预计这项研究将迅速导致新的和有效的临床治疗偏头痛。
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.
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DOI：
10.1002/anie.201411511
发表时间：
2015-03-16
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Akbulut Y;Gaunt HJ;Muraki K;Ludlow MJ;Amer MS;Bruns A;Vasudev NS;Radtke L;Willot M;Hahn S;Seitz T;Ziegler S;Christmann M;Beech DJ;Waldmann H
通讯作者：
Waldmann H
DOI：
10.1002/ajmg.b.32007
发表时间：
2012-01-01
影响因子：
2.8
作者：
Carreno, Oriel;Corominas, Roser;Macaya, Alfons
通讯作者：
Macaya, Alfons
影响因子：
6.5
作者：
Lee, Sang Hoon;Tonello, Raquel;Berta, Temugin
通讯作者：
Berta, Temugin
影响因子：
9.9
作者：
Cernuda-Morollon, Eva;Larrosa, Davinia;Pascual, Julio
通讯作者：
Pascual, Julio
DOI：
10.1038/nrd2757
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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