Solidagenone from Solidago chilensis Meyen Protects against Acute Peritonitis and Lipopolysaccharide-Induced Shock by Regulating NF-κB Signaling Pathway

Abstract

Anti-inflammatory agents are widely used for the treatment of inflammatory diseases. Nevertheless, the associated side effects of the available drugs make it necessary to search for new anti-inflammatory drugs. Here, we investigated the anti-inflammatory activity of solidagenone. Initially, we observed that a single dose of 30, 60, or 90 mg/kg of solidagenone did not result in mortality or elicit any discernible signs of toxicity in mice. At the same doses, solidagenone promoted a significant reduction in the migration of neutrophils in an acute peritonitis model and decreased mortality in a lipopolysaccharide-induced endotoxic shock model. Interestingly, treatment with solidagenone conferred a protective effect against leukopenia and thrombocytopenia, hematological disorders commonly observed in sepsis conditions. In addition, treatment with all the doses of solidagenone promoted a significant reduction in nitric oxide, TNF-α, and IL-1β levels relative to the LPS-stimulated vehicle-treated cultures. Furthermore, gene expression and in silico analyses also supported the modulation of the NF-κB pathway by solidagenone. Finally, in silico pharmacokinetics predictions indicated a favorable drugability profile for solidagenone. Taken together, the findings of the present investigation show that solidagenone exhibits significant anti-inflammatory properties in acute experimental models, potentially through the modulation of the NF-κB signaling pathway.

Keywords: NF-κB; endotoxic shock; inflammation; solidagenone.

Figure 1

Effect of solidagenone in a model of acute peritonitis. BALB/c mice (n = 6/group) were submitted to a challenge with 1% carrageenan solution after treatment with solidagenone (30, 60, and 90 mg/kg) or dexamethasone (Dexa; 30 mg/kg) or vehicle (saline solution with 10% DMSO). Naïve group consisted of untreated and unchallenged animals. Values represent the means ± S.D. of six mice/group. * p < 0.05 compared to the vehicle group; # p < 0.05 compared to the naïve group.

Figure 2

Survival curve of mice treated with solidagenone submitted to endotoxic shock. Mice were orally treated with solidagenone at doses of 30 mg/kg (■), 60 mg/Kg (▲), and 90 mg/kg (▼); dexamethasone at a dose of 30 mg/kg (♦); or vehicle (●). The results are from two experiments performed independently. * p < 0.05 compared to the vehicle group. ** p < 0.01 compared to the vehicle group. Statistical analyses were performed using the Logrank test (Mantel Cox).

Figure 3

In vivo treatment with solidagenone decreases nitric oxide, TNF-α, and IL-1β production by LPS-stimulated macrophages. Concentrations of nitrite (A), TNF-α (B), and IL-1β (C). Values represent the means ± S.D. of six mice/group. * p < 0.05 compared to the vehicle group; # p < 0.05 compared to naïve group. $ p < 0.05 compared to dexamethasone group.

Figure 4

Gene expression of NF-κβ in untreated macrophages or macrophages treated with solidagenone. Values represent the means ± S.D. of four determinations obtained in one of two experiments performed. * p < 0.05 compared to stimulated and untreated cells; # p < 0.05 compared to unstimulated and untreated cells; $ p < 0.05 compared to dexamethasone-treated cells.

Figure 5

Docking analysis of solidagenone binding to the p65 subunit of NF-κB. (a) Residues of the selected protein (PDB ID: 1NFI) and their interactions with solidagenone. (b) Two-dimensional interactions of solidagenone with amino acid residues in the p65 subunit of NF-κB.

Figure 6

Docking analysis of solidagenone binding to IKK domain. (a) Three-dimensional structure of selected protein (PDB ID: 4KIK) and its interaction with solidagenone. (b) Two-dimensional interactions of solidagenone with amino acid residues in the IKK domain.

Figure 7

SwissADME plot of drug-likeness of solidagenone. The pink area represents the optimal range for each property. For saturation (INSATU), the ratio of sp³ hybridized carbons over the total carbon count of the molecule (Fraction Csp3) should be at least 0.25. For size, the molecular weight should be between 150 and 500 g/mol. For polarity (POLAR), the TPSA should be between 20 and 130 Å. For solubility (INSOLU), log S should not exceed 6. For lipophilicity (LIPO), XLOGP3 should be in the range from −0.7 to +6.0. For flexibility (FLEX), the molecule should not have more than 9 rotatable bonds.