Anti-inflammatory effect of the spirocyclopiperazinium compound LXM-10 in mice and rats.
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.
Xiong
Yulan
Y
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, PR China.
Ye
Jia
J
Sun
Qi
Q
Zhao
Xia
X
Li
Runtao
R
Jiang
Yimin
Y
D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C547090:2,4-dimethyl-9-beta-phenylethyl-3-oxo-6, 9-diazaspiro(5.5)undecane chloride; D000893:Anti-Inflammatory Agents; D010879:Piperazines; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D015232:Dinoprostone