Nodakenin

Nodakenin suppresses lipopolysaccharide-induced inflammatory responses in macrophage cells by inhibiting tumor necrosis factor receptor-associated factor 6 and nuclear factor-κB pathways and protects mice from lethal endotoxin shock.[Pubmed: 22637723]

J Pharmacol Exp Ther. 2012 Sep;342(3):654-64.

Nodakenin, a coumarin isolated from the roots of Angelicae gigas, has been reported to possess neuroprotective, antiaggregatory, antibacterial, and memory-enhancing effects.
METHODS AND RESULTS:
In the present study, we investigated the anti-inflammatory effects of Nodakenin by examining its in vitro inhibitory effects on inducible nitric-oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse peritoneal macrophages and its in vivo effects on LPS-induced septic shock in mice. Our results indicate that Nodakenin concentration-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels, and these inhibitions cause attendant decreases in the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂). Furthermore, we found that Nodakenin inhibits the production and mRNA expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β induced by LPS. Molecular data revealed that Nodakenin suppressed the transcriptional activity and translocation of nuclear factor-κB (NF-κB) by inhibiting inhibitory κB-α degradation and IκB kinase-α/β phosphorylation. In addition, Nodakenin was found to significantly inhibit the LPS-induced binding of transforming growth factor-β-activated kinase 1 to tumor necrosis factor receptor-associated factor 6 (TRAF6) by reducing TRAF6 ubiquitination. Pretreatment with Nodakenin reduced the serum levels of NO, PGE₂, and proinflammatory cytokines and increased the survival rate of mice with LPS-induced endotoxemia.
CONCLUSIONS:
Taken together, our data suggest that Nodakenin down-regulates the expression of the proinflammatory iNOS, COX-2, TNF-α, IL-6, and IL-1β genes in macrophages by interfering with the activation of TRAF6, thus preventing NF-κB activation.

The effects of nodakenin on airway inflammation, hyper-responsiveness and remodeling in a murine model of allergic asthma.[Pubmed: 25090633]

Immunopharmacol Immunotoxicol. 2014 Oct;36(5):341-8.

Nodakenin is a major coumarin glucoside in the root of Peucedanum decursivum Maxim, a commonly used traditional Chinese medicine for the treatment of asthma and chronic bronchitis for thousands of years. In this work, the anti-asthma potential of Nodakenin was studied by investigation of its effect to suppress airway inflammation, hyper-responsiveness and remodeling in a murine model of chronic asthma.
METHODS AND RESULTS:
BALB/c mice sensitized to ovalbumin (OVA) were challenged with aerosolized OVA for 8 weeks, orally administered with Nodakenin at doses of 5, 10 and 20 mg/kg before each OVA challenge. Compared with the model group, Nodakenin treatment markedly inhibited airway inflammation, hyper-responsiveness and remodeling, showing improvement in subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia, and decreased levels of interleukin (IL)-4, IL-5, IL-13 and matrix metalloproteinase-2/-9 in bronchoalveolar lavage fluid, and the level of OVA-specific IgE in serum. In addition, the NF-κB DNA-binding activity in lung tissues was also reduced by Nodakenin treatment.
CONCLUSIONS:
These data indicated that Nodakenin might mitigate the development of chronic experimental allergic asthma.

Nodakenin, a coumarin compound, ameliorates scopolamine-induced memory disruption in mice.[Pubmed: 17382968 ]

Life Sci. 2007 May 1;80(21):1944-50.

Nodakenin is a coumarin compound initially isolated from the roots of Angelica gigas.
METHODS AND RESULTS:
In the present study, we investigated the effects of Nodakenin on learning and memory impairments induced by scopolamine (1 mg/kg, i.p.) using the passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Nodakenin (10 mg/kg, p.o.) administration significantly reversed scopolamine-induced cognitive impairments in the passive avoidance test and the Y-maze test (P<0.05), and also reduced escape latency during training in the Morris water maze test (P<0.05). Moreover, swimming times and distances within the target zone of the Morris water maze were greater in the Nodakenin-treated group than in the scopolamine-treated group (P<0.05). In an in vitro study, Nodakenin was found to inhibit acetylcholinesterase activity in a dose-dependent manner (IC(50)=84.7 microM). In addition, Nodakenin was also found to inhibit acetylcholinesterase activity for 6 h in an ex-vivo study.
CONCLUSIONS:
These results suggest that Nodakenin may be a useful for the treatment of cognitive impairment, and that its beneficial effects are mediated, in part, via the enhancement of cholinergic signaling.

Anti-Allergic Effects of Nodakenin in IgE/Ag-Induced Type I Hypersensitivity.[Reference: WebLink]

Journal of Life Science,2011,21(12):1721-5.

Mast cells are major effector cells associated with allergic responses. They are activated through the release of histamine, arachidonic acid, and proinflammatory cytokines.
METHODS AND RESULTS:
We investigated the effect of Nodakenin, derived from the roots of Angelica gigas Nakai, on mast cell degranulation and on an allergic response in an animal model. We also investigated the effect of Nodakenin on expression of multiple cytokines. Nodakenin suppressed the release of β-hexosaminidase, a marker of degranulation, as well as the expression of interleukin IL-4 and TNF-α mRNA. Nodakenin inhibited the passive cutaneous anaphylaxis (PCA) reaction in ICR mice in a dose-dependent manner.
CONCLUSIONS:
These results suggest that Nodakenin can inhibit mast cell degranulation through the inhibition of IL-4 and TNF-α mRNA expression, and that Nodakenin may potentially serve as an anti-allergic agent.

Inhibitory effects of nodakenin on the airway inflammation and NF-κB signaling pathway in a murine asthmatic model.[Reference: WebLink]

Effect of nodakenin on atopic dermatitis-like skin lesions.[Pubmed: 25209505]

Biosci Biotechnol Biochem. 2014;78(9):1568-71.

Nodakenin, derived from the roots of Angelica gigas Nakai, is an important natural resource and medicinal material with anti-allergic and anti- inflammatory activities. We have previously shown that Nodakenin inhibits IgE/Ag-induced degranulation in mast cells.
METHODS AND RESULTS:
In this study, we investigated the inhibitory effect of Nodakenin on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD)- like skin lesions in ICR mice. Scratching behavior, skin severity score, blood IgE level, and skin thickness were improved in DNCB-induced AD-like ICR mice. Our results showed that Nodakenin suppressed the increase of AD-like skin lesions in ICR mice.
CONCLUSIONS:
These results suggest that Nodakenin may be a potential therapeutic resource for AD as well as an adjunctive agent to control itching associated with AD.

Basic & Clinical Medicine, 2014 , 34 (5) :690-4.

To observe the effects of Nodakenin on airway inflammation in a mouse model of allergic asthma.
METHODS AND RESULTS:
BALB / c mice were assigned randomly to one of the following four experimental groups: control, model,Nodakenin and dexamethasone. All test mice were sensitized and challenged by OVA to induce airway inflammation. One hour before OVA challenge,Nodakenin group was intragastrically administered with Nodakenin at a dose of 10 mg / kg,and dexamethasone group was intraperitoneally injected with dexamethasone a dose of 1 mg / kg. Airway responsiveness was measured by a lung function analysis systems. The number of total leukocytes in BALF was counted using a hemocytometer,and differential cells were counted using Diff-Quick-stained smears. Histopathology of lung tissue was analyzed by Hematoxylin-eosin staining. Levels of inflammatory mediators in serum or BALFs were measured by ELISA. The activity and expression of proteins in NF-κB signaling pathway was respectively evaluated by EMSA and western blot analysis. Compared with control group,the model groupexhibited obvious airway inflammation,airway reactivity was significantly increased,the level of total cells and differential cells was significantly increased,levels of IL-4,IL-5,IL-13,IgE were significantly increased,levels of nuclear P65 and p-P65 protein was significantly enhanced,level of cytoplasmic P65 and IκBα protein was significantly decreased,and the NF-κB DNA binding activity was significantly increased. Compared with model group, Nodakenin significantly suppressed airway inflammation,airway hyperreactivity,reduced levels of IL-4,IL-5 and IL-13 in BALF,and IgE in serum,decreased levels of nuclear P65 and p-P65 protein,increased cytoplasmic P65 and IκBα protein,and increased the NF-κB DNA binding activity.
CONCLUSIONS:
Nodakenin efficiently inhibits antigen-induced airway inflammation in asthmatic mouse.