Anti-Inflammation of Spirocyclopiperazinium Salt Compound LXM-10 Targeting α7 nAChR and M4 mAChR and Inhibiting JAK2/STAT3 Pathway in Rats

作者：Zhang, Weiwei; Sun, Qi; Gao, Xiaoli; Jiang, Yimin; Li, Runtao; Ye, Jia^*

来源：PLos One, 2013, 8(6): e66895.

DOI：10.1371/journal.pone.0066895

• CYTOKINE PRODUCTION
• VAGUS NERVE
• TRANSCRIPTION
• SURVIVAL
• RELEASE
• STIMULATION
• ACTIVATION
• EXPRESSION
• ENDOTOXIN
• CNI-1493

The present study aims to investigate the therapeutic effects of LXM-10 by intragastric administration in both acute and chronic inflammatory models, and to explore the underlying molecular mechanisms. The results showed that LXM-10 produced significant anti-inflammatory effects on carrageenan induced paw edema and complete Freund's adjuvant (CFA) induced arthritis, in which LXM-10 inhibited paw swelling in a dose-and time-dependent manner. ELISA analysis showed the production of pro-inflammatory cytokines including TNF-alpha and IL-6 was decreased by LXM-10. Western blot analysis showed that LXM-10 significantly reduced phosphorylation of Janus kinase 2 (JAK2) and further blunted phosphorylation of signal transducer and activator of transcription-3 (STAT3). The effects that LXM-10 had shown were attenuated by methyllycaconitine citrate (an alpha 7 nicotinic acetylcholine receptor antagonist) or tropicamide (an M4 muscarinic acetylcholine receptor antagonist) in vivo. In conclusion, the studies showed that intragastric administration of LXM-10 exerted significant anti-inflammation effects in acute and chronic models, which may be attribute to the activation of alpha 7 nicotinic acetylcholine receptor and M4 muscarinic acetylcholine receptor, thereby inhibiting the JAK2/STAT3 signal pathway, and ultimately reducing the production of pro-inflammatory cytokines of TNF-alpha and IL-6.

• 出版日期2013-6-28
• 单位北京大学; 天然药物与仿生药物国家重点实验室