General Description

Dihydromyricetin exhibits potent anti-inflammatory properties through multiple mechanisms. Dihydromyricetin targets pathways such as NLRP-3, NF-κB, and cytokines, effectively reducing inflammation in various disease models including Alzheimer's, arthritis, and cardiovascular issues. By inhibiting NLRP-3 activation, suppressing NF-κB expression, and modulating cytokine levels, Dihydromyricetin shows promise as a therapeutic agent for inflammatory disorders. Its ability to dampen inflammatory responses and mitigate associated health complications underscores its potential clinical utility, despite limitations in bioavailability and chemical stability that warrant further research into safety and efficacy.

Figure 1. Dihydromyricetin

Overview

Dihydromyricetin, also known as Ampelopsis japonica (Thunb) Makino (AMP), was first discovered in 1940 from Nekemias meliaefolia. It's abundantly present in various plants like N. grossedentata, Vitis vinifera L., Myrica cerifera L., Prunus amygdalus Batsch, Ginkgo biloba L., Hovenia dulcis Thunb, and Cedrus deodara (Roxb. ex D.Don) G.Don. Dihydromyricetin degrades in weak alkaline environments, notably in the presence of Cu2+ and Fe3+, and has poor solubility, being soluble only in hot water and ethanol. Its efficacy is influenced by bioavailability, with animal studies indicating a 4.02% bioavailability in rats. Dihydromyricetin is primarily metabolized in the liver and gastrointestinal tract, with some absorbed into the bloodstream and distributed throughout the body. However, its low bioavailability and chemical instability limit its pharmacological and clinical applications. While few studies suggest Dihydromyricetin is non-toxic, further research is needed to fully understand its safety profile. ¹

Anti-inflammatory Mechanism

NLRP-3 and Pyroptosis

Dihydromyricetin has been shown to possess anti-inflammatory properties through its effects on the NLRP-3 (NOD-like receptor protein 3) signaling pathway and pyroptosis. Research indicates that Dihydromyricetin can ameliorate pyroptosis by activating the Nrf2 (NF-E2-related factor 2) signaling pathway, ultimately inhibiting the activation of NLRP-3 by reducing mitochondrial reactive oxygen species (ROS) levels in various cell types. In studies involving different conditions such as Alzheimer's disease (AD) and chronic liver injury, Dihydromyricetin treatment effectively suppressed the activation of caspase-1 and the expression of IL-1β, thereby dampening the inflammatory responses associated with these conditions. Furthermore, Dihydromyricetin demonstrated a protective effect against cardiovascular issues by inhibiting NLRP-3 activation, which is known to contribute to cardiotoxicity. Dihydromyricetin's ability to inhibit the activation of NLRP-3 in different disease models underscores its potential as a therapeutic agent for combating inflammatory responses and associated health complications. ²

Nuclear Factor-κB

Dihydromyricetin has been found to exhibit anti-inflammatory effects through its regulation of the Nuclear Factor-κB (NF-κB) pathway. Research has shown that Dihydromyricetin can down-regulate the expression of NF-κB by directly binding to IκB kinase (IKK), thereby inhibiting IKK phosphorylation. By inhibiting IKK phosphorylation, DHM can effectively suppress the NF-κB signal pathway. Dihydromyricetin has been shown to exert antiarthritic effects in collagen-induced arthritis rats by down-regulating NF-κB expression. Additionally, Dihydromyricetin has been found to inhibit the phosphorylation of IKKα/β dose-dependently in response to tumor necrosis factor-α (TNF-α), further supporting its anti-inflammatory properties. Furthermore, Dihydromyricetin has been shown to suppress NF-κB p65 phosphorylation, IKKβ activity, and IKKα/β phosphorylation in the NF-κB pathway, leading to inhibition of macrophage activation. Overall, Dihydromyricetin's ability to regulate the NF-κB pathway makes it a promising compound for the treatment of inflammatory disorders. ¹

Cytokines

Dihydromyricetin exhibits a potent anti-inflammatory mechanism mediated through various pathways, as elucidated by several studies. In LDL receptor-deficient mice, Dihydromyricetin was found to ameliorate liver and aorta inflammation by suppressing the expression of pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-6 (IL-6) (Liu et al., 2017b). Moreover, in rheumatoid arthritis rats, Dihydromyricetin demonstrated antioxidative properties by reducing oxidative stress and inhibiting the levels of TNF-α, IL-6, IL-1β, and cyclooxygenase-2 (COX-2) via activation of Nrf2 pathway (Chu et al., 2018). Furthermore, Dihydromyricetin attenuated TNF-α-mediated liver toxicity through the c-Jun N-terminal kinase (JNK) signaling pathway, thus preventing liver damage associated with inflammation (Xie et al., 2015). In diabetic cardiomyopathy mice, Dihydromyricetin treatment significantly lowered the levels of IL-6 and TNF-α, indicative of its anti-inflammatory effects (Wu et al., 2017). Similarly, in rats with pulmonary hypertension (PH), Dihydromyricetin suppressed the expression of IL-6 and TNF-α, suggesting its potential therapeutic utility in pulmonary inflammatory conditions (Li et al., 2017). Additionally, Dihydromyricetin inhibited the expression of IL-4, IL-5, and IL-13 in asthmatic mice, further highlighting its broad-spectrum anti-inflammatory activity (Xu et al., 2017). These findings collectively demonstrate the multifaceted anti-inflammatory properties of Dihydromyricetin, making it a promising candidate for the treatment of various inflammatory disorders. ¹

Reference

1. Sun Y, Liu S, Yang S, et al. Mechanism of Dihydromyricetin on Inflammatory Diseases. Front Pharmacol. 2022; 12: 794563.

2. Hu Q, Zhang T, Yi L, Zhou X, Mi M. Dihydromyricetin inhibits NLRP3 inflammasome-dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells. Biofactors. 2018; 44(2): 123-136.