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Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways.
Journal of Natural Products ( IF 5.1 ) Pub Date : 2020-03-09 , DOI: 10.1021/acs.jnatprod.9b01134
Elaine C D Gonçalves 1, 2 , Pollyana M Assis 3 , Laura A Junqueira 3 , Maíra Cola 1 , Adair R S Santos 4 , Nadia R B Raposo 3 , Rafael C Dutra 1, 2
Affiliation  

Citral ((2E)-3,7-dimethylocta-2,6-dienal), a bioactive component of lemongrass, inhibits oxidant activity, nuclear factor kappa B (NF-κB) activation, and cyclooxygenase-2 (COX-2) expression, even as it activates peroxisome proliferator-activated receptor (PPAR)-α and γ. Additionally, citral produces long-lasting inhibition of transient receptor potential (TRP) channels that are found in sensory neurons, such as TRPV1-3 and TRPM8, while it transiently blocks TRPV4 and TRPA1. Here, the effect of citral in experimental models of acute inflammation and hyperalgesia in mice, and the underlying citral mechanisms of action were investigated. ADMET properties and molecular targets were predicted using the online server. The immunomodulatory and antihyperalgesic effects of citral were evaluated, using mechanical and thermal stimuli, at different time-points on carrageenan, lipopolysaccharides (LPS), and zymosan-induced paw edema and hyperalgesia in mice. ADMET analysis ensures that the citral has not violated Lipinski's rule of five, indicating its safety consumption, and molecular target prediction software identified that citral is a potential fatty acid amide hydrolase (FAAH) inhibitor. Oral treatment with citral (50-300 mg/kg) significantly inhibited carrageenan-induced paw edema and thermal allodynia. Furthermore, citral modulated the inflammation induced by LPS and zymosan, toll-like receptor (TLR) 4, and TLR2/dectin-1 ligands, respectively. Moreover, pretreatment with cannabinoid receptor type 2 (CB2R) antagonists and ATP-sensitive K+ channel inhibitor, but not with a cannabinoid receptor type 1 (CB1R) antagonist, significantly reversed the anti-inflammatory effect of citral. Intriguingly, citral did not cause any relevant action in the central nervous system, and it was safe when assessed in a 14 day toxicity assay in male mice. Therefore, citral constitutes a promising, innovative, and safe molecule for the management of immunoinflammatory conditions and pain states.

中文翻译:

柠檬酸抑制小鼠的炎症反应和痛觉过敏:TLR4,TLR2 / Dectin-1和CB2大麻素受体/ ATP敏感性K +通道通路的作用。

柠檬草的生物活性成分柠檬醛((2E)-3,7-dimethylocta-2,6-dienal)抑制氧化剂活性,核因子κB(NF-κB)活化和环氧合酶2(COX-2)表达,即使它激活了过氧化物酶体增殖物激活受体(PPAR)-α和γ。此外,柠檬醛可持久抑制感觉神经元(如TRPV1-3和TRPM8)中发现的瞬时受体电位(TRP)通道,而瞬时阻断TRPV4和TRPA1。在这里,研究了柠檬醛在小鼠急性炎症和痛觉过敏实验模型中的作用以及潜在的柠檬醛作用机制。使用在线服务器预测了ADMET的性质和分子靶标。使用机械刺激和热刺激评估了柠檬醛的免疫调节和抗痛觉过敏作用,在角叉菜胶,脂多糖(LPS)和酵母聚糖诱导的小鼠爪水肿和痛觉过敏的不同时间点。ADMET分析可确保柠檬醛没有违反Lipinski的5规则,表明其安全性,分子目标预测软件确定柠檬醛是潜在的脂肪酸酰胺水解酶(FAAH)抑制剂。柠檬醛(50-300 mg / kg)口服治疗可显着抑制角叉菜胶诱发的爪水肿和热痛觉过敏。此外,柠檬醛分别调节了LPS和酵母聚糖,toll​​样受体(TLR)4和TLR2 / dectin-1配体诱导的炎症。此外,使用2型大麻素受体(CB2R)拮抗剂和ATP敏感的K +通道抑制剂进行预处理,但不使用1型大麻素受体(CB1R)拮抗剂进行预处理,大大逆转了柠檬醛的抗炎作用。有趣的是,柠檬醛对中枢神经系统没有引起任何相关作用,在雄性小鼠的14天毒性试验中评估它是安全的。因此,柠檬醛构成了用于治疗免疫炎性疾病和疼痛状态的有希望,创新和安全的分子。
更新日期:2020-03-09
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