Table 1.
Anti-inflammatory activity of menthol examined by human, in vivo, and in vitro studies.
| Main outcomes | Species/Subjects | Menthol dose, route, and duration of administration | specific organ/system | References |
|---|---|---|---|---|
| ↑TNF-α, IL-1β, and p-mTOR expression ↑intracellular Ca2+ concentration |
human bronchial epithelial cells (BEAS-2B) | 1 mmol/L, culture medium, 0.5, 1, 3, 6, 12, 24 hours | bronchus | Chen and Li (27) |
| ↓the release of TNF-α | THP-1 cell line | 1% ethanol concentration, culture medium, 2 hours | THP-1 cell | Hilfiger et al. (28) |
| ↓TNF-α expression ↓phosphorylation of p38 ↑IL-10 ↑phosphorylation of the extracellular-signal-regulated kinase ↑uptake of zymosan particles ↓cells with high phagocytic activity (more than three bound/ingested particles) ↓cell migration |
in vitro: F4/80+ macrophages in vivo: F4/80+ macrophages from WT and TRPM8-mutant C57BL/6 mice |
in vitro: 100 μmol/L, culture medium, 1h in vitro: 100 μmol/L, culture medium, 8h in vivo: 100 μmol/L, enemas, twice a day for 7 days |
colon | Khalil et al. (29) |
| ↓acrolein-induced TRPA1-dependent injury behavior ↓mechanical hyperalgesia |
wild-type mice | 50 nmol/50 μl, intraplantar injection, 10 minutes. 60 nmol/20 μl, intraplantar injection, 30 minutes before testing |
plantar surface of the hind paw | Liu et al. (6) |
| ↓sensory irritant response to acrolein ↓cyclohexanone-induced irritant response ↓respiratory irritation response ↑blood cotinine levels ↓active phases of inspiration and expiration |
female C57Bl/6J mice | Inspired concentration of 8, 40, 54 ppm, inhalation, 15 minutes | lung | Ha et al. (30) |
| ↓expression of COX-2 ↑level of GSH ↑activities of antioxidant enzymes including CAT, GST, GR and GPx ↓expression level of NF-κB ↓expressions of p38 and ERK |
48 female ICR mice | 20 and 80 mg/kg, applied onto the shaved area of dorsal skin, twice a week for 20 weeks | skin | Liu et al. (31) |
| ↑expression of TRPM8 ↑abnormal re-epithelialization, thickening of alveolar walls, and infiltration of inflammatory cells ↑BALF total protein ↑BALF total cell counts ↑BALF lymphocyte cell and neutrophil cell ↓BALF macrophage cell ↑BALF MIP-2 ↑lung MIP-2 ↑expression of 4-HNE ↑expression of ERK and JNK |
male C57BL/6J mice | 750 mL of fresh smoke generated from 1.5 Marlboro Black Menthol cigarettes, inhalation, 20 minutes per day for 1 week | lung | Lin et al. (32) |
| ↓intensity of Ca2+ influx ↓expression level of TRPV1 ↑body weight and food consumption ↓hyperplasia of the esophageal epithelium ↓levels of the inflammatory factors TNF-α, IL-6, and IL-1b |
Male C57BL/6 J mice | 50 mg/kg, p.o., 21 days | esophagus | Zhang et al. (33) |
| ↑cumulative survivals ↓cTnI levels ↓LVEDD and LVESD ↑EF and FS ↑dP/dtmax and dP/dtmin ↓elevation of neutrophil density and macrophage density ↓elevation of TNF-α, IL-1β, IL-6, MCP-1 ↑release of calcitonin gene-related peptide |
heterozygous knockout mice (generated by breeding TRPM8-/- mice with C57BL6/J wild-type mice) | 0.5%, mixed in chow diet as pre-treatment, 2 weeks | heart | Wang et al. (34) |
| ↑plasma cotinine concentrations ↓total and nonrenal clearance of nicotine ↓The ratio of nicotine glucuronide to nicotine in the urine |
14 healthy smokers | 61.4 mg/d, inhalation, 1 week | lung | Benowitz et al. (35) |
| ↓course of complete healing in napkin dermatitis ↓Erythema and pustules |
70 neonates with a diagnosis of candidial napkin dermatitis | 5% ethanol concentration, external skin use, twice a day for 7 days | skin | Sabzghabaee et al. (36) |
| ↓average ulcer area ↓infiltration of neutrophils into the gastric submucosa ↑expression of HSP-70 ↓expression of the apoptotic protein Bax ↓immunolabeled area ↓MPO activity ↑total glutathione levels ↑glutathione peroxidase activity ↑glutathione reductase activity ↓SOD enzyme ↓levels of cytokines ↓levels of TNF-α and IL-6 ↑level of IL-10 |
21 male Wistar rats | 50mg/kg, p.o., 2 hours | stomach | Rozza et al. (37) |
| ↑cold detection threshold and cold pain threshold ↑cold hyperalgesia assessments ↓warmth detection threshold and heat pain threshold ↓thermal sensory limen ↑superficial skin perfusion |
10 healthy subjects | 40% ethanol concentration, external skin use (volar forearm), 20 minutes | skin (volar forearm) | Olsen et al. (38) |
| ↓area of secondary mechanical hyperalgesia ↓secondary neurogenic flare |
14 healthy subjects | 40% ethanol concentration, external use, 20 minutes | skin | Andersen et al. (39) |
| ↓itch intensity (except for 32°C and 37°C) ↓neurogenic inflammation ↓wheal reactions |
13 healthy subjects | 40% ethanol concentration, external skin use, 7 minutes before itch induction | skin (volar forearm) | Andersen et al. (40) |
| ↓loss of body weight ↓macroscopic damage score, ulcer area, colon weight ↓colon length ↑reepithelization of the mucosal layer ↓edema ↓inflammatory cell infiltration in lamina propria ↑hematocrit ↓changes in MPO activity ↓IL-1β, IL-6 and TNF-α |
36 male Wistar rats | 20, 50, and 80 mg/kg, i.p., once a day for 3 days | colon | Ghasemi-Pirbaluti et al. (41) |
| ↓lung injury (with decreased values of mean linear intercept and destructive index) ↓decrease in values of body weights ↑spleen index ↓levels of AST and ALT ↓numbers of total white blood cells and macrophages ↓TNF-α, IL-1β, IL-6 ↓MPO and MDA levels ↑levels of GSH, GSH-Px, SOD, and T-AOC ↓expression of NF-κB p65 and p-p38 ↑expression of Nrf2 and NQO1 ↓expression of MMP-9, TIMP-1, CD4+ and CD8+ cells |
42 male SPF Sprague-Dawley rats | 5, 10, 20 mg/kg, i.p., 3 weeks | lung | Liu et al. (42) |
| ↓IBD-induced reduction in mean body weight, mean macroscopic and microscopic ulcer scores ↓activities of MPO and levels of MDA ↑glutathione level ↓levels of pro-inflammatory cytokines such as IL-1, IL-23, and TNF-α |
36 male albino Wistar rats | 50 mg/kg, p.o., 7 days and 10 days | colon | Bastaki et al. (43) |
| ↓rotational behavior of LPS-exposed rats ↓decrease in the number of tyrosine hydroxylase-positive cells ↑expression of tyrosine hydroxylase protein ↓microglial activation ↓upregulation of the pro-inflammatory enzymes COX-2 and iNOS at both the gene and protein levels ↓upregulating LPS-induced pro-inflammatory factors such as TNF-α, IL-6, and IL-1β (p38 excluded) ↓phosphorylation levels of NF-κB p65, AKT, ERK1/2, and JNK1/2 |
Male Wistar rats | 40% ethanol concentration, i.p., 4 weeks | microglia | Du et al. (44) |
| ↑mean BBB score ↑paw withdrawal threshold ↓caspase-3 immunoreactivity ↓apoptotic bodies ↑Arg-1 expression ↓GFAP, IBA-1, and TGF-β1 ↓collagen IV ↑brain-derived neurotrophic factor expression ↑expression of the growth cone marker ↓ANGPT-1 expression ↑GAP-43 expression ↓lesion area |
female Sprague-Dawley rats | 10 mg/kg, i.p., 2 weeks | Spinal Cord | Kim et al. (45) |
| ↓overall mortality ↓MDA and total nitrate/nitrite levels in the lung and kidney homogenates ↓TNF-α expression ↓immunoreactive cells ↑Bcl2-immunoreactivity ↑nuclear proliferating cell nuclear antigen immunoreactivity |
28 female Wistar rats | 100 mg/kg, p.o., 7 days | lung and kidney | Anter et al. (46) |
BBB score, Basso, Baettie, and Bresnahn score; Arg-1, Arginase-1; GFAP, glial fibrillary acidic protein; IBA-1, ionized calcium-binding adapter molecule-1; TGH-β1, transforming growth factor-β1; ANGPT-1, angiopoietin-1; GAP-43, growth-associated protein-43; N2a, Neuro2A; cTnl, cardiac troponin I; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; EF, eject fraction; FS, fractional shortening; Dp/dtmax, maximal rate of pressure development; Dp/dtmin, minimal rate of pressure decay; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; p-Mtor, phosphorylated-mammalian target of rapamycin; TRPA1, transient receptor potential A1; MDA, malondialdehyde; Bcl2, B-cell lymphoma-2; PCNA, proliferating cell nuclear antigen; MPO, myeloperoxidase; SOD, superoxide dismutase; COX, cyclo-oxygen-ase, Inos, inductible nitric oxide synthase; AKT, protein kinase B; ERK, extracellular regulated protein kinase; JNK, c-Jun N-terminal kinase; GSH, glutathione; GSH-Px, glutathione peroxidase; CAT, catalase; GST, glutathione s-transferase; GR, glutathione reductase; GPx, glutathione peroxidase; BALF, bronchoalveolar lavage fluid; T-AOC, total antioxidant capacity; NF-κB, nuclear factor kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; NQO1, NAD(P)H: quinone oxidoreductase 1.