The antishock effect of anisodamine requires the upregulation of alpha7 nicotine acetylcholine receptors by IL-10.

摘要

AIMS: 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 alpha7 nicotinic acetylcholine receptors (alpha7 nAChR). Because IL-10 is a critical anti-inflammatory factor, we investigated its potential role in the antishock action of anisodamine. MAIN METHODS: C57BL/6 and IL-10 -/- mice were intraperitoneally administered LPS and/or anisodamine, and the 24h survival rate, cytokine production and alpha7 nAChR expression were examined. In addition, RAW264.7 cells were stimulated with LPS, anisodamine and/or IL-10, and cytokine production and alpha7 nAChR expression were investigated. KEY FINDINGS: 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-alpha and IL-1beta 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 alpha7 nAChR expression, which was further augmented in the presence of anisodamine. Spleens from IL-10 -/- mice expressed significantly lower alpha7 nAChRs levels compared to IL-10 +/+ mice. Although anisodamine markedly increased the expression of alpha7 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. SIGNIFICANCE: These findings demonstrate that IL-10 plays an important role in the antishock action of anisodamine. It acts through upregulating alpha7 nAChR synergistically with anisodamine.