title: The antishock effect of anisodamine requires the upregulation of α7 nicotine acetylcholine receptors by IL-10.
abstract: OBJECTIVE
  Although anisodamine, a muscarinic acetylcholine receptor antagonist, has been used in China for treating various shocks for many years, the mechanisms are not well understood. Our previous studies have demonstrated anisodamine exerts its cholinergic anti-inflammatory action through indirectly activating α7 nicotinic acetylcholine receptors (α7 nAChR). Because IL-10 is a critical anti-inflammatory factor, we investigated its potential role in the antishock action of anisodamine.
  
  
  METHODS
  C57BL/6 and IL-10 -/- mice were intraperitoneally administered LPS and/or anisodamine, and the 24h survival rate, cytokine production and α7 nAChR expression were examined. In addition, RAW264.7 cells were stimulated with LPS, anisodamine and/or IL-10, and cytokine production and α7 nAChR expression were investigated.
  
  
  RESULTS
  Anisodamine dose-dependently increased the 24h survival rate of C57BL/6 mice treated with LPS. The antishock role of anisodamine was significantly attenuated in IL-10 -/- mice. Anisodamine significantly decreased TNF-α and IL-1β production in LPS-treated RAW264.7 cells and C57BL/6 mice. However, it did not increase the level of IL-10 in the same experiments. In RAW264.7 cells, IL-10 treatment increased α7 nAChR expression, which was further augmented in the presence of anisodamine. Spleens from IL-10 -/- mice expressed significantly lower α7 nAChRs levels compared to IL-10 +/+ mice. Although anisodamine markedly increased the expression of α7 nAChRs in spleens from LPS-treated IL-10 +/+ mice, it only induced a marginal increase of the receptor in spleens from LPS-treated IL-10 -/- mice.
  
  
  CONCLUSIONS
  These findings demonstrate that IL-10 plays an important role in the antishock action of anisodamine. It acts through upregulating α7 nAChR synergistically with anisodamine.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Lei
authors.forename: Aijun
authors.initials: A
authors.lastname: Liu
authors.forename: Yili
authors.initials: Y
authors.lastname: Yang
authors.forename: Dingfeng
authors.initials: D
authors.lastname: Su
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002681:China; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D012991:Solanaceous Alkaloids / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000316:Adrenergic alpha-Agonists; C579166:Chrna7 protein, mouse; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011978:Receptors, Nicotinic; D012991:Solanaceous Alkaloids; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C003922:anisodamine; D016753:Interleukin-10