The anti-inflammatory and antinociceptive effects of NF-kappaB inhibitory guanidine derivative ME10092.
The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine) is known to possess anti-radical and anti-ischemic activity but its molecular targets have not been identified. This study investigated whether ME10092 regulates the nuclear factor kappa B (NF-kappaB)-mediated signal transduction in vivo. The effect of ME10092 treatment (1-100 pmol/mouse) on nuclear translocation of NF-kappaB, activation of expression of inflammatory mediators and production of nitric oxide were measured in the lipopolysaccharide (LPS)-induced brain inflammation model in mice in vivo. The antinociceptive activity of ME10092 was tested in the formalin-induced paw licking test. ME10092 dose-dependently inhibited LPS-induced nuclear translocation of NF-kappaB, transcription of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Electron paramagnetic resonance measurements showed that ME10092 inhibited the LPS-induced increase in nitric oxide content in mouse brain tissue in a dose-dependent manner. In the formalin-induced paw licking test, ME10092 (at the dose of 3mg/kg, p.o. twice daily for eight days) significantly reduced nociceptive response. In conclusion, above results indicate that ME10092 inhibits NF-kappaB activation and suppresses the up-regulation of inflammatory mediators in experimental models in vivo.
Dambrova
Maija
M
Latvian Institute of Organic Synthesis, Riga, Latvia. md@biomed.lu.lv
Zvejniece
Liga
L
Skapare
Elina
E
Vilskersts
Reinis
R
Svalbe
Baiba
B
Baumane
Larisa
L
Muceniece
Ruta
R
Liepinsh
Edgars
E
D000284:Administration, Oral; D000700:Analgesics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology; D005557:Formaldehyde; D006146:Guanidines / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010147:Pain Measurement / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C408693:1-(3,4-dimethoxy-2--chlorobenzylideneamino)guanidine; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006146:Guanidines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D005557:Formaldehyde; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2