Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice.

Cinder Faith Cohen,Arthur Silveira Prudente,Temugin Berta,Sang Hoon Lee

doi:10.3389/fnmol.2021.765181

Abstract

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.

Highlights

Migraine is a recurrent headache disorder affecting about 15% of the worldwide population with severe impact on patients’ lives, substantive healthcare costs, and loss of productivity (Vos et al, 2016)
Because Englerin A has been reported to potentially activate TRPC5 (Akbulut et al, 2015), too, we administered ML204 (40 μg), a specific TRPC4 antagonist, and observed that it significantly reduced the duration of wipes (Figure 1C), suggesting that activation of TRPC4 is involved in pain
We have shown that TRPC4 is highly expressed in cutaneous peptidergic sensory neurons in the trigeminal ganglia, a key structure implicated in the generation of migraine (Goadsby, 2009)

Summary

Introduction

Migraine is a recurrent headache disorder affecting about 15% of the worldwide population with severe impact on patients’ lives, substantive healthcare costs, and loss of productivity (Vos et al, 2016). While mechanisms leading to various symptoms are still incompletely known, transient receptor potential (TRP) channels are emerging as promising therapeutic targets for migraine (Dussor et al, 2014; Benemei and Dussor, 2019). A number of these channels, including transient receptor potential cation channel subfamily A, member 1 (TRPA1); subfamily V, member 1 (TRPV1), subfamily V, member 4 (TRPV4), and subfamily M, member 8 (TRPM8) are highly expressed in primary sensory neurons and play a role in migraine (Dussor et al, 2014; Benemei and Dussor, 2019). Preclinical data support the activation of TRPA1 in migraine mechanisms such as increased dural blood flow and neurogenic vasodilatation via the release of calcitonin generelated peptide (CGRP), a neuropeptide for which monoclonal antibodies have been recently FDA-approved for the treatment of migraine (Tso and Goadsby, 2017)

Methods

Results

Conclusion