The permeability enhancing mechanism of menthol on skin lipids: a molecular dynamics simulation study

Abstract

The stratum corneum (SC), the outermost layer of skin, represents the primary barrier to molecules penetrating the skin. Menthol is widely used in clinical medicine as a penetration enhancer due to its high efficiency and relative safety. In this study, molecular dynamics simulations have been performed to investigate the effect of menthol molecules on the structural and permeability of both single component and ternary mixed bilayers. The lipid matrix is modeled as pure ceramide (CER2) or as a 2:2:1 mixture of CER2, cholesterol (CHOL), and free fatty acid (FFA). The effect of menthol on the SC bilayer was investigated at various concentrations of menthol. For both models, the area per lipid decreases and the membrane thickness increases with increased menthol concentration, which may be due to the fact that menthol molecules penetrate into the bilayer and aggregate at the bilayer center. As for ternary mixed bilayer at high concentration, the lipids rearranged, and one more layer formed inside the former two leaflets. Our simulation results are consistent with the experimental evidence that high concentrations of menthol fluidize the SC lipids and enhance permeability. The penetration enhancement of menthol may take place through direct interactions with lipids rather than by forming water pores. Graphical abstract The effect of menthol on the structural and permeability of skin lipids was investigated using a molecular dynamics simulation method. Increased menthol concentration makes the area per lipid decrease and the membrane thickness increase. Our results show that the penetration enhancement of menthol may take place through direct interactions with lipids.

The permeability of magnesium across the skin is enhanced by menthol cream

“…We showed that levomenthol increased the permeation of Mg ++ across porcine skin substantially. This is consistent with earlier data indicating that menthol has penetration enhancing properties [5,6]. However, the increase in Mg ++ skin permeability was not evident during the first hours in this experimental model, indicating that in clinical use Mg ++ -levomenthol cream should be applied on skin on regular basis to obtain any meaningful absorption.…”

“…The permeability of the skin can be increased by the excipients termed permeation enhancers. Menthol is one compound with penetrationenhancing properties [5]. Menthol is a natural fat-soluble terpene that can permeate the epidermis.…”

“…Menthol is a natural fat-soluble terpene that can permeate the epidermis. Menthol enhances transdermal penetration of other substances through the outermost layer of the skin by interacting with intracellular lipids and therefore interfering with the lipid structure [5]. It might also act as an enhancer via calcium ion interactions [6].…”

Effective Release of Intracellular Enzymes by Permeating the Cell Membrane with Hydrophobic Deep Eutectic Solvents

“…As a penetration reagent, menthol has an excellent affinity for the hydrophobic lipid tails. The presence of menthol proved to improve the permeability of the cell membrane by interacting with lipids directly, perturbing the lipid tails to varying degrees . We hypothesized that the hydrophobic DESs could first act on the outer membrane, and thus, destabilize its structure.…”

Cellular Base of Mint Allelopathy: Menthone Affects Plant Microtubules

“…This allows two interpretations: the microtubule elimination could act upstream and release a cellular response leading to a unspecific permeabilization of the membrane, or, inversely, menthone/ isomenthone could lead to a permeabilization of the membrane that would kill the cells and, secondarily, cause a breakdown of microtubules. There are several arguments against the second scenario: first, the biological effect is specific with respect to structure: the structurally closely related menthol is much less effective as compared to menthone/isomenthone (Figures 3, 4, and 6), although it is very efficient as membrane permeabilizer (Wang and Meng, 2017). Along the same line, menthone/isomenthone is effective at lower dosage in BY-2 cells overexpressing the TuB6-GFP marker as compared to the non-transformed WT ( Figure 4C) which speaks against unspecific membrane permeabilization as primary cause for microtubule elimination.…”