Modified derivatives of natural products have led to many significant therapeutic advances. Menthol contains a naturally occurring cyclic monoterpene alcohol that can be found in several plants, particularly in the mint family, it is a common ingredient in a wide range of commercial products, and it also has medicinal value due to its anti-cancer, analgesic, and anti-inflammatory effects. Some research suggests that menthyl esters may possess unique advantages compared to other anti-obesity and anti-inflammatory compounds due to their specific mechanisms of action that contribute to their dual effects making them particularly effective in addressing inflammatory and metabolic conditions.
“The functional components of plants that contribute to human health have always intrigued me. Discovering new molecules from natural materials inspired our research team to develop these amino acid derivatives of menthol, “said Professor Gen-ichiro Arimura from the Department of Biological Science and Technology, Tokyo University of Science, Japan.
For this study, the researchers developed and investigated menthyl esters of valine (MV) and isoleucine (MI), which are derived from menthol by replacing its hydroxyl group with valine and isoleucine, respectively. Beginning by synthesizing menthyl esters of 6 amino acids, and subsequently assessing the properties of these esters using in vitro cell lines, then finally conducting mice experiments to investigate the effects under induced disease conditions.
According to the researchers, the exceptional anti-inflammatory profiles of MV and MI were determined by assessing the transcript levels of tumor necrosis factor-α (Tnf) in stimulated macrophage cells. Remarkably, both MV and MI outperformed menthol in the anti-inflammatory assay, and RNA sequencing analysis revealed that 18 genes involved in inflammatory and immune responses were effectively suppressed.
Further investigation into the mechanism of action of the menthyl esters revealed that liver X receptor (LXR) — an intracellular nuclear receptor, had an important role in the anti-inflammatory effects and this was independent of the cold-sensitive transient receptor TRPM8, which primarily detects menthol. Investigating even further into the LXR-dependant activation of MV and MI, they found that Scd1 gene — central to lipid metabolism was upregulated by LXR. Moreover, in mice with induced intestinal colitis, the anti-inflammatory effects were further validated with suppressed transcript levels of Tnf and Il6 genes by MV or MI, in an LXR-dependent manner.
Motivated by the discovery of the LXR-SCD1 intracellular machinery, the researchers hypothesized that the menthyl esters to possess anti-obesity properties, finding that the esters inhibit adipogenesis-fat accumulation, specifically at the mitotic clonal expansion stage in 3T3-L1 adipocyte cells. During animal studies, the diet-induced obesity in mice was ameliorated and adipogenesis was suppressed.
“Although this study focused on their functions and mechanisms of action in diseases modeled after inflammation and obesity, we expect that these compounds will also be effective against a wide range of lifestyle-related diseases caused by metabolic syndrome, such as diabetes and hypertension, as well as allergic symptoms,” said Arimura.
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