Plant-derived polyphenols attenuate lipopolysaccharide-induced nitric oxide and tumour necrosis factor production in murine microglia and macrophages.
Lipopolysaccharides released during bacterial infections induce the expression of pro-inflammatory cytokines and lead to complications such as neuronal damage in the CNS and septic shock in the periphery. While the initial infection is treated by antibiotics, anti-inflammatory agents would be advantageous add-on medications. In order to identify such compounds, we have compared 29 commercially available polyphenol-containing plant extracts and pure compounds for their ability to prevent LPS-induced up-regulation of NO production. Among the botanical extracts, bearberry and grape seed were the most active preparations, exhibiting IC(50) values of around 20 mug/mL. Among the pure compounds, IC(50) values for apigenin, diosmetin and silybin were 15, 19 and 12 muM, in N-11 murine microglia, and 7, 16 and 25 muM, in RAW 264.7 murine macrophages, respectively. In addition, these flavonoids were also able to down-regulate LPS-induced tumour necrosis factor production. Structure-activity relationships of the flavonoids demonstrated three distinct principles: (i) flavonoid-aglycons are more potent than the corresponding glycosides, (ii) flavonoids with a 4'-OH substitution in the B-ring are more potent than those with a 3'-OH-4'-methoxy substitution, (iii) flavonoids of the flavone type (with a C2=C3 double bond) are more potent than those of the flavanone type (with a at C2-C3 single bond).
Shanmugam
Kirubakaran
K
Biochemistry and Molecular Biology, James Cook University, Townsville, Australia. Fax: + 61-7-4781-6078.
Holmquist
Lina
L
Steele
Megan
M
Stuchbury
Grant
G
Berbaum
Katrin
K
Schulz
Oliver
O
Benavente García
Obdulio
O
Castillo
Julián
J
Burnell
Jim
J
Garcia Rivas
Vernon
V
Dobson
Geoff
G
Münch
Gerald
G
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D059808:Polyphenols; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects
D005419:Flavonoids; D008070:Lipopolysaccharides; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide