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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Stroke | Research

Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol

Authors: Shiang-Suo Huang, Hsing-Hui Su, Szu-Yu Chien, Hsin-Yi Chung, Sih-Ting Luo, Yu-Ting Chu, Yi-Hsin Wang, Iona J. MacDonald, Hsun-Hua Lee, Yi-Hung Chen

Published in: Journal of Neuroinflammation | Issue 1/2022

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Abstract

Background

No reports exist as to neuroprotective effects associated with topical activation of transient receptor potential melastatin 8 (TRPM8), a noted cold receptor. In the present study, we identified whether activating peripheral TRPM8 can be an adjuvant therapy for ischemic stroke.

Methods

Menthol, an agonist of TRPM8, was applied orally or topically to all paws or back of the mouse after middle cerebral artery occlusion (MCAO). We used Trpm8 gene knockout (Trpm8−/−) mice or TRPM8 antagonist and lidocaine to validate the roles of TRPM8 and peripheral nerve conduction in menthol against ischemic stroke.

Results

Application of menthol 16% to paw derma attenuated infarct volumes and ameliorated sensorimotor deficits in stroke mice induced by MCAO. The benefits of topically applied menthol were associated with reductions in oxidative stress, neuroinflammation and infiltration of monocytes and macrophages in ischemic brains. Antagonizing TRPM8 or Trpm8 knockout dulls the neuroprotective effects of topically application of menthol against MCAO. Immunohistochemistry analyses revealed significantly higher TRPM8 expression in skin tissue samples obtained from the paws compared with skin from the backs, which was reflected by significantly smaller infarct lesion volumes and better sensorimotor function in mice treated with menthol on the paws compared with the back. Blocking conduction of peripheral nerve in the four paws reversed the neuroprotective effects of topical menthol administrated to paws. On the other hand, oral menthol dosing did not assist with recovery from MCAO in our study.

Conclusion

Our results suggested that activation of peripheral TRPM8 expressed in the derma tissue of limbs with sufficient concentration of menthol is beneficial to stroke recovery. Topical application of menthol on hands and feet could be a novel and simple-to-use therapeutic strategy for stroke patients.
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Metadata
Title
Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol
Authors
Shiang-Suo Huang
Hsing-Hui Su
Szu-Yu Chien
Hsin-Yi Chung
Sih-Ting Luo
Yu-Ting Chu
Yi-Hsin Wang
Iona J. MacDonald
Hsun-Hua Lee
Yi-Hung Chen
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Stroke
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02553-4

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