Anti-TRPM8 monoclonal antibody, clone FQS5207

Background: Topical application of menthol is a popular form of cold therapy and chemically triggers cold receptors and increases cutaneous blood flow. However, although cutaneous blood flow increases, it remains unknown where this increase arises from. Intramuscular temperature assessment may indirectly indicate a change in muscular blood flow. Purpose: To establish intramuscular temperature, blood flow responses and subjective temperature sensation following application of menthol-based cooling gel to the anterior thigh. Study design: Controlled, randomized cross over interventional study Methods: Twenty (age: 21.4 + 1.7) healthy males were treated on three separate days in random order with ice, a menthol-based gel or placebo gel (participant single blinded) on one anterior thigh. All measurements were taken at baseline and for 80 mins following treatment: 1) Skin, core, and intramuscular temperatures (1 & 3 cm deep); 2) femoral arterial blood flow (duplex ultrasound); 3) cutaneous blood flow (laser Doppler) and 4) subjective cold sensation. Results: Ice and both gels decreased (p < 0.0001, CI (Ice): -5.2 to -6.2 and CI (gels) -1.4 to -2.5) intramuscular temperature by 5.7 and 1.9 degrees C respectively, but by 80 mins were similar to each other (1.5-2 degrees C less than pre-treatment). Skin temperature mirrored muscle temperature with 8.8 and 4.2 degrees C respective decline for ice and gels. Menthol gel increased (p < 0.0001) cutaneous blood flow by 0.3 ml/min compared to unaltered flow associated with the placebo gel and a decline of 0.3 ml/min for the ice. Menthol gel cold sensation was subjectively reported to be cooler (p < 0.0001) than the other two treatments. Core temperature and arterial flow were unaffected. Conclusion: This is the first study to demonstrate the intramuscular cooling effect of menthol-based gel. However, the likely cause was from evaporative cooling despite menthol-derived increases in cutaneous blood flow and cooling sensation.

In human uveal melanoma (UM), tumor enlargement is associated with increases in aqueous humor vascular endothelial growth factor-A (VEGF-A) content that induce neovascularization. 3-Iodothyronamine (3-T(1)AM), an endogenous thyroid hormone metabolite, activates TRP melastatin 8 (TRPM8), which blunts TRP vanilloid 1 (TRPV1) activation by capsaicin (CAP) in human corneal, conjunctival epithelial cells, and stromal cells. We compare here the effects of TRPM8 activation on VEGF-induced transactivation of TRPV1 in an UM cell line (92.1) with those in normal primary porcine melanocytes (PM) since TRPM8 is upregulated in melanoma. Fluorescence Ca2+-imaging and planar patch-clamping characterized functional channel activities. CAP (20 mu M) induced Ca2+ transients and increased whole-cell currents in both the UM cell line and PM whereas TRPM8 agonists, 100 mu M menthol and 20 mu M icilin, blunted such responses in the UM cells. VEGF (10 ng/ml) elicited Ca2+ transients and augmented whole-cell currents, which were blocked by capsazepine (CPZ; 20 mu M) but not by a highly selective TRPM8 blocker, AMTB (20 mu M). The VEGF-induced current increases were not augmented by CAP. Both 3-T(1)AM (1 mu M) and menthol (100 mu M) increased the whole-cell currents, whereas 20 mu M AMTB blocked them. 3-T(1)AM exposure suppressed both VEGF-induced Ca2+ transients and increases in underlying whole-cell currents. Taken together, functional TRPM8 upregulation in UM 92.1 cells suggests that TRPM8 is a potential drug target for suppressing VEGF induced increases in neovascularization and UM tumor growth since TRPM8 activation blocked VEGF transactivation of TRPV1.