Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, PR China.
Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, PR China; Thadweik Academy of Medicine, Beijing 100039, PR China.
Int Immunopharmacol. 2014 May;20(1):229-37. doi: 10.1016/j.intimp.2014.03.004. Epub 2014 Mar 19.
The simultaneous use of drugs with different mechanisms of anti-inflammatory action is a strategy for achieving effective control of inflammation while minimizing dose-related side effects. Choline was described to potentiate the antinociceptive action of aspirin at small doses in several inflammatory pain models. However, these findings are only limited to alleviating pain, more associated data are required to confirm the effectiveness of the combined choline and aspirin therapy against inflammatory disorders. Moreover, no report is available regarding the mechanism responsible for their synergism. Here, we first investigated the anti-inflammatory activity and pharmacological mechanisms of co-administration of choline and aspirin in 2 commonly studied inflammation models, carrageenan-induced paw edema and lipopolysaccharide (LPS)-induced sepsis in mice. Isobolographic analysis revealed that combined choline and aspirin administration exhibited a strong synergistic interaction in reducing carrageenan-mediated edema, and the estimated combination index values at 50%, 75%, and 90% effective dose (ED50, ED75, and ED90) were 0.25, 0.32, and 0.44. Drug co-administration also afforded synergistic protection against LPS-induced sepsis and mortality, since aspirin or choline alone was inadequate to improve survival. The effects of choline-aspirin co-administration were blocked by methyllycaconitine, suggesting that activation of alpha 7 nicotinic acetylcholine receptor participates in the interaction between choline and aspirin. Furthermore, co-administration of choline and aspirin was more likely to inhibit the production of pro-inflammatory mediators induced by LPS. Our results indicated that combined choline and aspirin therapy represented a significant synergistic interaction in attenuating acute inflammatory response. This preclinical relevant evidence provides a promising approach to treat inflammation-based diseases such as arthritis and sepsis.
同时使用具有不同抗炎作用机制的药物是一种策略，可以在最小化剂量相关副作用的同时实现有效的炎症控制。胆碱已被描述为在几种炎症性疼痛模型中小剂量增强阿司匹林的镇痛作用。然而，这些发现仅局限于缓解疼痛，需要更多相关数据来确认联合胆碱和阿司匹林治疗对炎症性疾病的有效性。此外，尚无关于其协同作用机制的报告。在这里，我们首先在两种常用的炎症模型（角叉菜胶诱导的爪肿胀和脂多糖（LPS）诱导的败血症）中研究了胆碱和阿司匹林联合给药的抗炎活性和药理学机制。等辐射分析表明，联合胆碱和阿司匹林给药在减轻角叉菜胶介导的水肿方面表现出强烈的协同相互作用，在 50%、75%和 90%有效剂量（ED50、ED75 和 ED90）时的估计组合指数值分别为 0.25、0.32 和 0.44。胆碱-阿司匹林联合给药也提供了对抗 LPS 诱导的败血症和死亡率的协同保护作用，因为阿司匹林或胆碱单独不足以提高生存率。胆碱-阿司匹林联合给药的作用被甲基-利卡灵阻断，表明α7 烟碱型乙酰胆碱受体的激活参与了胆碱和阿司匹林之间的相互作用。此外，胆碱和阿司匹林联合给药更有可能抑制 LPS 诱导的促炎介质的产生。我们的结果表明，联合胆碱和阿司匹林治疗在减轻急性炎症反应方面表现出显著的协同相互作用。这种临床前相关证据为治疗关节炎和败血症等基于炎症的疾病提供了一种有前景的方法。
