Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that can occur in people with acute or chronic liver disease. Here, we investigated the effects of menthol, a natural monoterpene, on HE induced by thioacetamide (TA) in male Wistar rats. The rats received 200 mg/kg of TA twice a week for four weeks and were administered 10 mg/kg of menthol intraperitoneally daily for the same period. The results showed that menthol treatment reduced oxidative stress and inflammation in the livers and hippocampi of the rats that received TA. It also lowered the levels of ammonium and liver enzymes AST, ALT, ALP, and GGT in the serum of these animals and prevented liver histopathological damage. In addition, the expression and activity of acetylcholinesterase in the hippocampus of HE model rats were decreased by menthol. Likewise, this monoterpene reduced the expression of TLR4, MyD88, and NF-κB in the hippocampus while increasing the expression of BDNF and α7-nACh receptor. Menthol also reduced neuronal death in the hippocampal cornu ammonis-1 and dentate gyrus regions and reduced astrocyte swelling, which led to improved learning and spatial memory in rats with HE. In conclusion, the study suggests that menthol may have strong protective effects on the liver and brain, making it a potential treatment for HE and neurodegenerative diseases.

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise.ClinicalTrials.gov Identifier: NCT05467631.

UNASSIGNED: This research aims to investigate the protective action of menthol dissolved in dimethyl sulfoxide (DMSO) on experimental epileptiform activity induced by the intraperitoneal (IP) injection of pentylenetetrazol (PTZ) in male rats.
UNASSIGNED: Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to five equal groups. The control animals received normal saline (200 μL) and the rest four cohorts were considered as treatment. Menthol was dissolved in DMSO and intraperitoneally injected at the doses of 100, 200, and 400 mg/kg into the first, second, and third groups (M100, M200, and M400 V=200 μL), respectively. The fourth treatment was injected with the solvent (200 μL). The animals were anesthetized, then underwent cranial surgery and a recording electrode was implanted in the stratum radiatum of the hippocampal carbonic anhydrase 1 (CA1) region (AP=-2.76 mm, ML=-1.4 mm and DV=3 mm). The seizure activity was induced by PTZ (IP) and assessed by counting and measuring amplitudes of the spikes for 10 minutes using the eTrace program.
UNASSIGNED: Menthol was observed to significantly reduce the activity level of PTZ-induced epileptiform activity, as well as exert a protective and inhibitory action on proconvulsant effect of DMSO in a dose-dependent manner.
UNASSIGNED: Menthol can potentially be used as an adjuvant to prevent seizure activity.
UNASSIGNED: Dimethyl sulfoxide (DMSO) induces proconvulsant effects, significantly increasing spike counts.Menthol 100 mg/kg also stimulates seizure activity, leading to a substantial spike count increase.Menthol 200 and 400 mg/kg exhibit inhibitory effects, decreasing seizure activity and spike counts.
UNASSIGNED: In this study, we explored the potential protective effects of menthol, dissolved in dimethyl sulfoxide (DMSO), on experimentally induced epileptiform activity in male rats. Our research involved thirty adult male Wistar rats, divided into five groups. While the control group received normal saline, the remaining four groups were treated with different doses of menthol in DMSO. The rats underwent surgery, and electrodes were implanted in the hippocampal region for recording. Using pentylenetetrazol (PTZ) to induce seizure activity, we observed that menthol, administered at varying doses, significantly reduced the level of epileptiform activity triggered by PTZ. Notably, menthol also demonstrated a protective and inhibitory effect on the proconvulsant action of DMSO, and this effect was dose-dependent. In simpler terms, our findings suggest that menthol has the potential to be used as an additional treatment to prevent seizure activity. This means that incorporating menthol, especially at specific doses, may offer a protective influence against epileptic events. This research sheds light on a promising avenue for potential therapeutic interventions, emphasizing the importance of further exploration of menthol\'s role in epilepsy prevention. Ultimately, our study opens the door to considering menthol as a valuable component in the development of strategies to mitigate the impact of seizures.

Transient receptor potential (TRP) melastatin member 8 (TRPM8) is a non-selective cation channel that can be activated by low temperatures (8-26 °C), cooling agents (including menthol analogs such as menthol, icilin, and WS-12), voltage, and extracellular osmotic pressure changes. TRPM8 expression has been identified in the digestive system by several research teams, demonstrating its significant involvement in tissue function and pathologies of the digestive system. Specifically, studies have implicated TRPM8 in various physiological and pathological processes of the esophagus, stomach, colorectal region, liver, and pancreas. This paper aims to comprehensively outline the distinct role of TRPM8 in different organs of the digestive system, offering insights for future mechanistic investigations of TRPM8. Additionally, it presents potential therapeutic targets for treating conditions such as digestive tract inflammation, tumors, sensory and functional disorders, and other related diseases. Furthermore, this paper addresses the limitations of existing studies and highlights the research prospects associated with TRPM8.

Ketoprofen is a non-steroidal, anti-inflammatory drug frequently incorporated in topical dosage forms which are an interesting alternatives for oral formulations. However, due to the physiological barrier function of skin, topical formulations may require some approaches to improve drug permeation across the skin. In this study, ketoprofen-loaded microemulsion-based gels with the addition of menthol, commonly known for absorption-enhancing activity in dermal products, were investigated. The main objective of this study was to analyze the physicochemical properties of the obtained gels in terms of topical application and to investigate the correlation between the gel composition and its mechanical properties and the drug release process. Microemulsion composition was selected with the use of a pseudoternary plot and the selected systems were tested for electrical conductivity, viscosity, pH, and particle diameter. The polymer gels obtained with Carbopol® EZ-3 were subjected to rheological and textural studies, as well as the drug release experiment. The obtained results indicate that the presence of ketoprofen slightly decreased yield stress values. A stronger effect was exerted by menthol presence, even though it was independent of menthol concentration. A similar tendency was seen for hardness and adhesiveness, as tested in texture profile analysis. Sample cohesiveness and the drug release rate were independent of the gel composition.

OBJECTIVE: Brown adipose tissue (BAT) thermogenesis has profound energy-expanding potential, which makes it an attractive target tissue to combat ever-increasing obesity and its other associated metabolic complications. Although it is fairly accepted that cold is a potent inducer of BAT activation and function, there are limited studies on the mechanisms of pharmacological cold-mimicking agents, such as the TRPM8 agonist, menthol, on BAT thermogenesis and activation.
METHODS: Herein, we sought to determine the effect of topical application of menthol (10% w/v [4 g/kg] cream formulation/day for 15 days) on temperature sensitivity behaviour (thermal gradient assay, nesting behaviour), adaptive thermogenesis (infrared thermography, core body temperature), BAT sympathetic innervation (tyrosine hydroxylase immunohistochemistry) and activation (18F-FDG PET-CT analysis, Uncoupling Protein 1 immunohistochemistry and BAT gene expression), whole-body energy expenditure (indirect calorimetry) and other metabolic variables in male C57BL/6N mice.
RESULTS: We show that male C57BL/6N mice: (a) develop a warm-seeking and cold-avoiding thermal preference phenotype; (b) display increased locomotor activity and adaptive thermogenesis; (c) show augmented sympathetic innervation in BAT and its activation; (d) exhibit enhanced gluconeogenic capacity (increased glucose excursion in response to pyruvate) and insulin sensitivity; and (e) show enhanced whole-body energy expenditure and induced lipid-utilizing phenotype after topical menthol application.
CONCLUSIONS: Taken together, our findings highlight that pharmacological cold mimicking using topical menthol application presents a potential therapeutic strategy to counter weight gain and related complications.

The United States (US) Food and Drug Administration\'s (FDA) regulatory oversight over electronic cigarettes (e-cigs) includes access restriction for persons <21 years of age and flavor restrictions for \"cartridge-based\" products. Despite the restrictions, consumption by US youth perseveres. Studies on youth e-cig use are limited by the reliability and accuracy of self-reports. As an alternative to self-reports, the current study examined nicotine, cannabinoid, and unlabeled e-cigs and other vaping products confiscated from Virginia public schools to characterize trends among students. Findings highlight a shift from JUUL and pod-based products to single use disposable e-cigs following the FDA flavor restrictions on cartridge-based e-cigs. Chemical analysis of e-liquids by gas chromatography-mass spectrometry identified a wide variety of flavorants and an increase in the prevalence of synthetic coolants. Most confiscated products were nicotine salt formulations, but the prevalence of cannabinoid-based vaping products increased. The popularity of flavored disposable e-cigs highlights the need for further restrictions to reduce youth consumption. The increasing use of synthetic coolants instead of menthol may suggest that manufacturers are employing tactics to bypass regulations. Continued youth access to e-cigs and the abundance of cannabinoid-based products is problematic from health and safety perspectives. Continued research incorporating confiscated product analysis can be used to understand youth access to vaping products and evolutions in manufacturing practices.

Leukemia is one of the most deadly cancers in Thailand. Natural compounds have been developed for cancer treatment. Menthol, a peppermint compound, has shown pharmacological properties such as anti-cancer activity. However, the mechanism of menthol inducing extracellular vesicles in leukemic cells is not yet understood. In this study, we investigated the effects of menthol on leukemic extracellular vesicles and their role in apoptosis. NB4 and Molt-4 leukemic cells were cultured with menthol in various concentrations and times. Bioinformatic analysis was used to investigate target proteins of extracellular vesicle and apoptosis, followed by mRNA and protein expression by RT‒PCR and western blotting, respectively. Our findings indicate that menthol inhibits leukemic cell proliferation and increases extracellular vesicles. Furthermore, menthol treated leukemic extracellular vesicles induce apoptosis and upregulate the expression of ATG3 and caspase-3 in both mRNA and protein levels. These results suggest that menthol has an antileukemic effect through ATG3 and caspase-3 in apoptosis of leukemic extracellular vesicles.

Transient receptor potential melastatin 8 (TRPM8) is a temperature- and menthol-sensitive ion channel that contributes to diverse physiological roles, including cold sensing and pain perception. Clinical trials targeting TRPM8 have faced repeated setbacks predominantly due to the knowledge gap in unraveling the molecular underpinnings governing polymodal activation. A better understanding of the molecular foundations between the TRPM8 activation modes may aid the development of mode-specific, thermal-neutral therapies. Ancestral sequence reconstruction was used to explore the origins of TRPM8 activation modes. By resurrecting key TRPM8 nodes along the human evolutionary trajectory, we gained valuable insights into the trafficking, stability, and function of these ancestral forms. Notably, this approach unveiled the differential emergence of cold and menthol sensitivity over evolutionary time, providing a fresh perspective on complex polymodal behavior. These studies provide a paradigm for understanding polymodal behavior in TRPM8 and other proteins with the potential to enhance our understanding of sensory receptor biology and pave the way for innovative therapeutic interventions.