Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol

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.

A randomized, double‐blinded, vehicle‐controlled clinical trial of topical cryosim‐1, a synthetic TRPM8 agonist, in prurigo nodularis

“…22 In this context, topical activation of peripheral TRPM8 showed neuroprotective effects and mitigated ischemic stroke in mice. 23 Furthermore, TRPM8 is involved in energy homeostasis, and TRPM8 agonists could be potential novel agents for treating obesity. 24 The mechanism of action of TRPM8 agonists in the treatment of PN is not yet known.…”

“…Interestingly, topical application of menthol to healthy volunteers activated TRPM8 and increased cutaneous blood flow not only at the site of application but also across the dermatome 22 . In this context, topical activation of peripheral TRPM8 showed neuroprotective effects and mitigated ischemic stroke in mice 23 . Furthermore, TRPM8 is involved in energy homeostasis, and TRPM8 agonists could be potential novel agents for treating obesity 24 …”

Menthol Pretreatment Alleviates Campylobacter jejuni-Induced Enterocolitis in Human Gut Microbiota-Associated IL-10−/− Mice

“…( Figure 5 A). In support, menthol application could decrease infiltration of infected brain tissues with respective innate immune cell subsets during brain ischemia [ 48 ]. Furthermore, C. jejuni -induced increases in colonic T lymphocytes could be reversed to basal values in menthol-treated mice ( Figure 5 C).…”

Para‑hydroxybenzaldehyde against transient focal cerebral ischemia in rats via mitochondrial preservation

“…Under normal physiological conditions, ROS regulates the operation of the mitochondrial redox signaling pathway (58). However, when transient focal cerebral ischemia occurs, T-SOD, a key antioxidant enzyme, cannot normally scavenge excess oxygen free radicals due to its reduced activity, resulting in excessive ROS-oxidized lipids in the mitochondria (59). MDA is a product of lipid peroxidation that directly reflects the level of oxidative stress (60)(61)(62).…”