TRP Channel Agonists for Aging

(TRP Trial)

Overseen By Sue K Slimak, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Penn State University

Must not be taking: Calcium channel blockers

Disqualifiers: Pregnancy, Nicotine use, Skin allergies, Diabetes, others

Compensation: Varies

Number of Visits: 1

Duration: Single session

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how certain skin treatments affect blood flow and nerve responses. It uses topical gels with ingredients like menthol, capsaicin, and camphor, found in mint, chili peppers, and other common plants. These ingredients act as TRP channel agonists, specifically targeting TRPM8, TRPV4, and TRPV1 channels. The goal is to determine how these temperature-reactive ingredients can influence skin health as people age. Individuals without skin allergies, who do not use nicotine, and are not diabetic might be suitable for the study. As an Early Phase 1 trial, this research aims to understand how these treatments work in people, offering participants a chance to contribute to groundbreaking skin health research.

Will I have to stop taking my current medications?

The trial requires that you do not use calcium channel blockers or regularly use topical analgesics containing menthol, camphor, or capsaicin. If you are using these, you may need to stop.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that certain substances, like menthol and capsaicin, have been studied for their effects when applied to the skin. Menthol, known for its cooling sensation, does not affect core body temperature or blood flow, indicating it is well-tolerated. Capsaicin is used safely in treatments for pain relief, such as joint pain, and is generally considered safe.

Camphor, another substance studied, is commonly used in creams for muscle pain and has a history of safe use. However, the current study is in its early stages, focusing mainly on safety. This phase helps researchers understand how well these treatments are tolerated, but a complete safety profile will develop as more data is collected. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they target the TRP channels, which play a crucial role in sensory perception and aging processes. Unlike typical treatments that might focus on lifestyle changes or systemic drugs, these treatments use TRP channel agonists like menthol, capsaicin, and camphor in topical gels to directly stimulate specific receptors in the skin. This localized approach could offer faster results and fewer side effects. Additionally, by activating TRPM8, TRPV4, and TRPV1 channels, these treatments may uniquely influence cellular aging processes, potentially offering a novel way to combat aging-related changes at the cellular level.

What evidence suggests that this trial's treatments could be effective for neurovascular responses in the skin?

This trial will compare different TRP channel agonists for their effects on aging. Research has shown that special channels in the skin, such as TRPM8, TRPV4, and TRPV1, react to temperature and natural substances like menthol, capsaicin, and camphor. Participants may receive a topical gel containing menthol, which activates TRPM8, increases blood flow in the skin, and helps control body temperature. Others may receive a gel with capsaicin, found in chili peppers, which may slow aging in blood vessels. Another group will receive a gel with camphor, which affects TRPV1 and is known for its soothing effects and potential benefits for skin aging. These channels play a role in sensing temperature, pain, and other sensations, which could benefit skin health and aging. ^{2 3 5 6 7}

Who Is on the Research Team?

Lacy Alexander, Ph.D.

Principal Investigator

Penn State University

Are You a Good Fit for This Trial?

This trial is for individuals interested in how certain substances affect skin responses, particularly as they age. There are no specific inclusion or exclusion criteria provided, so participants may need to be generally healthy and willing to have substances applied to their skin.

Inclusion Criteria

Women must not be pregnant and/or breastfeeding

Exclusion Criteria

Body mass index exceeding 35kg*m-2

I have skin allergies or a current skin condition.

I am currently taking calcium channel blockers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Topical application of TRP channel agonists including menthol, capsaicin, and camphor to examine neurovascular responses

Single session

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

What Are the Treatments Tested in This Trial?

Interventions

• TRPM8 Agonist
• TRPM8, TRPV4, TRPV1 Agonists
• TRPV1 Agonist
• TRPV4 Agonist

Trial Overview The study tests the effects of gels that activate TRP channels in the skin—these are parts of cells responsive to temperature and natural compounds in mint, chili peppers, garlic, etc. It looks at how menthol (mint), capsaicin (chili pepper), and camphor impact skin's blood flow and nerves.

How Is the Trial Designed?

Group I: Transient Receptor Potential M8 V4 V1 Agonist Experimental Treatment 1 Intervention

Topical menthol 10%, capsaicin 0.05%, camphor 0.6% applied once

Group II: Transient Receptor Potential (V4) Agonist Experimental Treatment 1 Intervention

Topical capsaicin gel applied once at 0.05%

Group III: Transient Receptor Potential (V1) Agonist Experimental Treatment 1 Intervention

Topical camphor gel applied once at 0.6%

Group IV: Transient Receptor Potential (M8) Agonist Experimental Treatment 1 Intervention

Topical menthol gel applied once at 10%

Group V: no gel Active Control 1 Intervention

no gel comparison

Group VI: Vehicle Gel Placebo Group 1 Intervention

Non-active topical gel

Who Is Running the Clinical Trial?

Penn State University

Lead Sponsor

Trials

380

Recruited

131,000+

Published Research Related to This Trial

A novel compound derived from nutmeg, identified as erythro- and threo-Δ8'-7-ethoxy-4-hydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan, acts as a potent agonist for the TRPM8 ion channel with an EC50 of 0.332 μM, indicating its potential for use in cold sensation and pain relief.

The study also found that a derivative of this compound is even more potent (EC50 = 11 nM), and when combined with l-(-)-menthol, they produce an additive effect, suggesting they may activate TRPM8 through different mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound. Shirai, T., Kumihashi, K., Sakasai, M., et al.[2020]

The study identified 10 new agonists for the TRPM8 channel, which is activated by cooling substances like menthol, with icilin being the most potent at an EC50 of 0.2 µM.

Unlike the VR1 channel, which is activated by low pH, TRPM8 is inhibited by protons, indicating a distinct mechanism of action between these two related channels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Behrendt, HJ., Germann, T., Gillen, C., et al.[2018]

Research over the past two decades highlights the role of transient receptor potential (TRP) channels in pain perception, leading to the development of new pain therapies targeting these channels.

While TRPV1 antagonists have faced challenges due to side effects related to temperature sensation, new small molecule antagonists for TRPA1 and TRPM8 are advancing in clinical trials, showing promise for treating inflammatory and neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Moran, MM., Szallasi, A.[2021]

Research on TRPV1 and related TRP channels has revealed their crucial roles in pain signaling and temperature sensation, leading to increased interest in developing small molecule drugs that target these channels for therapeutic use.

The pharmaceutical industry is actively working on creating effective TRP channel modulators, particularly for pain management, with potential applications also in treating conditions like urinary incontinence and certain cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic targeting of TRP channels--the TR(i)P to pain relief. Eid, SR.[2022]

Transient Receptor Potential (TRP) channels, particularly TRPV1-4, TRPA1, and TRPM8, are key players in pain detection and modulation, making them promising targets for developing new pain relief medications.

Several TRP-targeting agents, including capsaicin and menthol, have been used as analgesics, while new compounds are currently being tested for their efficacy and safety in treating inflammatory and neuropathic pain, with attention to their effects on thermosensation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transient receptor potential channels - emerging novel drug targets for the treatment of pain. Sałat, K., Moniczewski, A., Librowski, T.[2019]

TRPM8 is an important ion channel that responds to cold temperatures and various compounds, playing a role in several health issues like migraines and obesity, which suggests it could be a target for new treatments.

Recent research has focused on developing TRPM8 agonists and antagonists, providing insights into their potential therapeutic applications and the structural understanding of the TRPM8 channel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Progress in TRPM8 Modulation: An Update. González-Muñiz, R., Bonache, MA., Martín-Escura, C., et al.[2020]

TRPC4 and TRPC5 proteins form important ion channels in the body that are involved in various physiological and pathological processes, making them potential targets for treating conditions like cancer, epilepsy, and pain.

Recent research has identified several selective small-molecule modulators of TRPC1/4/5 channels, including both agonists and antagonists, which could aid in understanding their functions and contribute to drug discovery for related human diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels. Rubaiy, HN.[2021]

TRPM8 is a key cold temperature sensor in the body, and its antagonists are being explored as potential treatments for pain and bladder disorders.

A new series of compounds, particularly Compound 45, showed strong efficacy in reducing pain responses in rat models, with effective doses under 3 mg/kg, indicating promising pharmacological properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists. Horne, DB., Tamayo, NA., Bartberger, MD., et al.[2017]

Newly developed menthol derivatives are highly selective and potent agonists for the TRPM8 ion channel, showing up to six-fold higher potency and two-fold increased efficacy compared to menthol.

These compounds do not activate other thermo-TRP channels, making them promising candidates for therapeutic applications in pain relief and cancer treatment, as they can specifically target TRPM8 without unwanted side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. Sherkheli, MA., Vogt-Eisele, AK., Bura, D., et al.[2019]

Mutating tyrosine 745 (Y745) on the TRPM8 channel significantly affects the inhibition of cold- and voltage-activated currents by the antagonist SKF96365, highlighting its importance in menthol sensitivity.

Other TRPM8 antagonists, like BCTC, do not rely on Y745 for their inhibitory effects, suggesting that there are multiple binding sites on the TRPM8 channel, which could inform the development of more targeted drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential role of the menthol-binding residue Y745 in the antagonism of thermally gated TRPM8 channels. Malkia, A., Pertusa, M., Fernández-Ballester, G., et al.[2021]

A new class of TRPM8 antagonists has been discovered that shows effectiveness in reducing cold hypersensitivity, which is a common symptom in neuropathic pain.

These antagonists demonstrated in vivo efficacy in a rat model of neuropathic pain induced by chronic constriction injury, suggesting their potential as therapeutic agents for treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of vinylcycloalkyl-substituted benzimidazole TRPM8 antagonists effective in the treatment of cold allodynia. Calvo, RR., Meegalla, SK., Parks, DJ., et al.[2012]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8791073/

Menthol-induced activation of TRPM8 receptors increases ... These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0378427417300796

Activation of the cold-receptor TRPM8 by low levels ... In this study, we have analyzed both the contents of menthol and other natural TRPM8 agonists in tobacco products and developed a bioassay to ...

3. science.org science.org/doi/10.1126/sciadv.adm9228

Evidence that the cold- and menthol-sensing functions of ... TRPM8 is a temperature- and menthol-sensitive ion channel that contributes to diverse physiological roles, including cold sensing and pain perception.

4. link.springer.com link.springer.com/article/10.1007/s13105-025-01120-8

TRPM8-driven thermogenesis by menthol: mechanisms of ... Menthol significantly raised core body temperature, improved cold tolerance, and reduced cold injury severity in treated mice. Network ...

5. elifesciences.org elifesciences.org/articles/70153

Dysfunctional TRPM8 signalling in the vascular response ... Cold detecting thermoreceptor TRPM8's signalling is diminished with ageing which leads to an impaired response to cold observed in ageing.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6044592/

INFLUENCE OF TOPICALLY APPLIED MENTHOL ... 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.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06444594

NCT06444594 | Transient Receptor Potential Channels The aim of the study is to examine how topically applied TRP channel agonists including menthol, capsaicin and camphor impact neurovascular responses in the ...