Inhibition of inflammatory cytokine production and protection against endotoxin toxicity by benzydamine.
The present study was designed to assess the effect of N,N-dimethyl-3-[(1-benzyl-1H-indazol-3-yl)ossi]-1-propana mine (benzydamine) on in vivo and in vitro production of inflammatory cytokines. Benzydamine inhibited tumour necrosis factor-alpha (TNF-alpha) production in vitro by human lipopolysaccharide-stimulated monocytes with an ED50 of approximately 25 microM (12 donors). Under the same conditions, benzydamine had modest or no effect on production of interleukin (IL-1), IL-6 and IL-8. Inhibition of TNF-alpha production was not restricted to LPS in that similar results were obtained using inactivated streptococci. Inhibition of TNF production was associated with a modest (about 30% at 50 microM, 7 donors) reduction of mRNA. A similar inhibition of TNF-alpha production was also detected with mouse peritoneal macrophages. With mouse cells benzydamine also substantially inhibited IL-1 production in vitro. In vivo treatment with benzydamine (40 mg/kg s.c.) protected mice against LPS lethality. Protection against septic shock was observed when benzydamine was administered before or concomitantly with LPS. Protection against LPS toxicity was associated with a marked reduction of serum levels of TNF-alpha and IL-1 beta, whereas IL-6 was unaffected. Inhibition of inflammatory cytokine production may play a role in the anti-inflammatory activity of benzydamine and provide suggestions for novel therapeutic applications.
Sironi
M
M
Istituto Ricerche Farmacologiche Mario Negri, Milano, Italy.
Pozzi
P
P
Polentarutti
N
N
Benigni
F
F
Coletta
I
I
Guglielmotti
A
A
Milanese
C
C
Ghezzi
P
P
Vecchi
A
A
Pinza
M
M
Mantovani
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001591:Benzydamine / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001591:Benzydamine