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Anti-inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE2.Ki Mice Fed a High-Fat Diet

Anti-inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE2.Ki Mice Fed a High-Fat Diet

Amna Abderrazak, Dominique Couchie, Dler Faieeq Darweesh Mahmood, Rima Elhage, Cécile Vindis, Muriel Laffargue, Véronique Matéo, Berthold Büchele, Monica Rubio Ayala, Menna El Gaafary, Tatiana Syrovets, etc.

Circulation. 2015 Mar 24;131(12):1061-70.

PMID: 25613820

Abstract:

Background:
This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE2Ki mice fed a high-fat Western-type diet.
Methods and results:
Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1β and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal-activated cultured mouse peritoneal macrophages, with a maximum effect at ≈50 nmol/L and EC50 values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3(-/-) macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE2.Ki mice fed a high-fat diet resulted in a decreased IL-1β plasma level compared with vehicle-treated mice (5.2±1.0 versus 11.7±1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% (P=0.02) and 41% (P=0.02), respectively.
Conclusions:
Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2.Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP84692911	Arglabin		84692-91-1	Price

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