Molecular Mechanisms Underlying the Anti-Inflammatory Properties of (R)-(-)-Carvone: Potential Roles of JNK1, Nrf2 and NF-κB

Abstract

To explore the molecular mechanisms underlying the anti-inflammatory activity of (R)-(-)-carvone, we evaluated its ability to inhibit the signaling pathways involving the mitogen-activated protein kinases (MAPKs) and the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). (R)-(-)-carvone significantly decreased c-Jun N-terminal kinase (JNK) 1phosphorylation, but not that of the other MAPKs, induced by bacterial lipopolysaccharides (LPS) in the RAW 264.7 macrophage cell line. Although (R)-(-)-carvone significantly inhibited resynthesis of the inhibitor of NF-κB (IκB)-α induced by LPS, it did not interfere with the canonical NF-κB activation pathway, suggesting that it may interfere with its transcriptional activity. (R)-(-)-carvone also showed a tendency to decrease the levels of acetylated NF-κB/p65 in the nucleus, without affecting the activity and protein levels of Sirtuin-1, the major NF-κB/p65 deacetylating enzyme. Interestingly, the nuclear protein levels of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the expression of its target,, heme oxygenase-1 (HO-1), an antioxidant enzyme, also showed a tendency to increase in the presence of (R)-(-)-carvone. Taken together, these results suggest that the ability of (R)-(-)-carvone to inhibit JNK1 and to activate Nrf2 can underlie its capacity to inhibit the transcriptional activity of NF-κB and the expression of its target genes. This study highlights the diversity of molecular mechanisms that can be involved in the anti-inflammatory activity of monoterpenes.

Plant Monoterpenes and Essential Oils as Potential Anti-Ageing Agents: Insights from Preclinical Data

“…For instance, carvacrol [118], citral [122], geraniol [126], perillyl alcohol [129,130], thymol [132], among others (Table 5) interfered with the canonical activation of NF-κB, blocking its nuclear translocation and, consequently, its transcriptional activity. On the other hand, some monoterpenes did not interfere directly with NF-κB activation but promoted the activation of other molecules, namely SIRT1 and Nrf2, which antagonize the transcriptional activity of NF-κB [119][120][121]131]. Examples of these compounds include (S)-(+)-carvone [119], (R)-(−)-carvone [120], 1,8-cineole [121] and perillaldehyde [131].…”

“…On the other hand, some monoterpenes did not interfere directly with NF-κB activation but promoted the activation of other molecules, namely SIRT1 and Nrf2, which antagonize the transcriptional activity of NF-κB [119][120][121]131]. Examples of these compounds include (S)-(+)-carvone [119], (R)-(−)-carvone [120], 1,8-cineole [121] and perillaldehyde [131]. Other signaling pathways were also evaluated, namely MAPK and inflammasome NLRP3 that include menthol [128] and hinokitiol [127], respectively.…”