Anti-inflammatory effect of the spirocyclopiperazinium compound LXM-10 in mice and rats.

Abstract

Anti-inflammatory drugs are clinically limited because of their side effects. The aim of this study was to evaluate the anti-inflammatory activities and mechanisms of the spirocyclopiperazinium compound LXM-10 (2, 4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro[5.5]undecane chloride). We found that LXM-10 produced a significant, dose-dependent decrease in xylene- and carrageenin-induced edema. The anti-inflammatory effect was attenuated by hexamethonium, methyllycaconitine citrate, atropine methylnitrate, and tropicamide. The serum level of TNF-alpha was reduced by LXM-10 in lipopolysaccharide-challenged mice, and this effect was also inhibited by methyllycaconitine and tropicamide. LXM-10 also reduced the prostaglandin E(2) concentration in rat paw tissue. LXM-10 minimised the carrageenin-induced pathological changes and did not affect mice heart rate. LXM-10 did not induce significant changes in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) activity. Median lethal dose (LD(50)) of LXM-10 was 1573.0 micromol/kg. Our findings suggest that LXM-10 has anti-inflammatory effects by activating alpha7 nicotinic and M(4) muscarinic acetylcholine receptors with limited side effects.

• Authors: Yulan Xiong, Jia Ye, Qi Sun, Xia Zhao, Runtao Li, Yimin Jiang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 626 Issue 2-3 Pg. 290-6 (Jan 25 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 19836382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro(5.5)undecane chloride
• Anti-Inflammatory Agents
• Piperazines
• Receptors, Muscarinic
• Receptors, Nicotinic
• Spiro Compounds
• Tumor Necrosis Factor-alpha
• Aspartate Aminotransferases
• Alanine Transaminase
• Alkaline Phosphatase
• Dinoprostone

Topics

• Alanine Transaminase (metabolism)
• Alkaline Phosphatase (metabolism)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use, toxicity)
• Aspartate Aminotransferases (metabolism)
• Dinoprostone (metabolism)
• Female
• Heart Rate (drug effects)
• Inflammation (drug therapy, metabolism, pathology, physiopathology)
• Male
• Mice
• Piperazines (pharmacology, therapeutic use, toxicity)
• Rats
• Receptors, Muscarinic (metabolism)
• Receptors, Nicotinic (metabolism)
• Spiro Compounds (pharmacology, therapeutic use, toxicity)
• Tumor Necrosis Factor-alpha (blood)