The anti-inflammatory and antinociceptive effects of NF-kappaB inhibitory guanidine derivative ME10092.

Abstract

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.

• Authors: Maija Dambrova, Liga Zvejniece, Elina Skapare, Reinis Vilskersts, Baiba Svalbe, Larisa Baumane, Ruta Muceniece, Edgars Liepinsh
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 10 Issue 4 Pg. 455-60 (Apr 2010) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 20074673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• 1-(3,4-dimethoxy-2--chlorobenzylideneamino)guanidine
• Analgesics
• Anti-Inflammatory Agents, Non-Steroidal
• Guanidines
• Inflammation Mediators
• Interleukin-1beta
• Lipopolysaccharides
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Formaldehyde
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2

Topics

• Administration, Oral
• Analgesics
• Animals
• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase 2 (biosynthesis)
• Encephalitis (drug therapy, immunology)
• Formaldehyde
• Guanidines (pharmacology)
• Inflammation Mediators (metabolism)
• Interleukin-1beta (biosynthesis)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• NF-kappa B (antagonists & inhibitors)
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase Type II (biosynthesis)
• Pain Measurement (drug effects)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)
• Tumor Necrosis Factor-alpha (biosynthesis)