Xiaoli Gao1,2, Qi Sun3, Weiwei Zhang1,4, Yimin Jiang5, Runtao Li3, Jia Ye6. 1. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China. 2. Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China. 3. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China. 4. Clinical Pharmacy of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People's Republic of China. 5. Centre of Medical and Health Analysis, Peking University, Beijing, 100191, People's Republic of China. 6. Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People's Republic of China. yejia@bjmu.edu.cn.
Abstract
OBJECTIVE: This study aimed to investigate the anti-inflammatory effects of a novel spirocyclopiperazinium salt compound LXM-15, and explore the underlying mechanisms. METHODS: Xylene-induced mouse ear oedema and carrageenan-induced rat paw oedema tests were used to evaluate the anti-inflammatory effects of LXM-15. The protein levels of TNF-α, IL-6, phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were detected by ELISA or Western blot analysis. Additionally, receptor blocking test was performed to explore the possible target. RESULTS: Intragastric administration with LXM-15 (2, 1, 0.5 mg/kg in mice, and 6, 3, 1.5 mg/kg in rats) produced distinct anti-inflammatory effects in vivo, the highest inhibition percentage was 60 and 52%, respectively (P < 0.01). Following treatment with LXM-15 (6 mg/kg, i.g.), the levels of TNF-α and IL-6 in the rats paws were attenuated by 40 and 41%; and the phosphorylation of JAK2 and STAT3 was restrained by 35 and 45%, respectively (P < 0.01). All effects of LXM-15 were blocked by pretreatment with methyllycaconitine citrate or tropicamide. CONCLUSION: This study provides the first report that the spirocyclopiperazinium salt compound LXM-15 displays considerable anti-inflammatory effects. The underlying mechanism may be through activating the peripheral α7 nicotinic acetylcholine receptor and M4 muscarinic acetylcholine receptor, leading to the inhibition of the JAK2/STAT3 signalling pathway, eventually resulting in the reduction of TNF-α and IL-6.
OBJECTIVE: This study aimed to investigate the anti-inflammatory effects of a novel spirocyclopiperazinium salt compound LXM-15, and explore the underlying mechanisms. METHODS:Xylene-induced mouseear oedema and carrageenan-induced ratpaw oedema tests were used to evaluate the anti-inflammatory effects of LXM-15. The protein levels of TNF-α, IL-6, phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were detected by ELISA or Western blot analysis. Additionally, receptor blocking test was performed to explore the possible target. RESULTS: Intragastric administration with LXM-15 (2, 1, 0.5 mg/kg in mice, and 6, 3, 1.5 mg/kg in rats) produced distinct anti-inflammatory effects in vivo, the highest inhibition percentage was 60 and 52%, respectively (P < 0.01). Following treatment with LXM-15 (6 mg/kg, i.g.), the levels of TNF-α and IL-6 in the rats paws were attenuated by 40 and 41%; and the phosphorylation of JAK2 and STAT3 was restrained by 35 and 45%, respectively (P < 0.01). All effects of LXM-15 were blocked by pretreatment with methyllycaconitine citrate or tropicamide. CONCLUSION: This study provides the first report that the spirocyclopiperazinium salt compound LXM-15 displays considerable anti-inflammatory effects. The underlying mechanism may be through activating the peripheral α7 nicotinic acetylcholine receptor and M4 muscarinic acetylcholine receptor, leading to the inhibition of the JAK2/STAT3 signalling pathway, eventually resulting in the reduction of TNF-α and IL-6.
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