A Novel Compound C12 Inhibits Inflammatory Cytokine Production and Protects from Inflammatory Injury <em>In Vivo</em>

Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases.炎症是众多疾病的标志性病理特征。尽管类固醇类药物与环氧合酶抑制剂（cyclooxygenase inhibitors）是临床常用的主流抗炎治疗药物，但该类药物往往会引发严重不良反应。因此，研发非类固醇类抗炎药物具有迫切的临床需求。本团队在前期研究中已设计并合成了一种新型水溶性化合物C12（2,6-双(4-(3-(二甲氨基)丙氧基)亚苄基)环己酮），将其作为抗炎候选药物。本研究旨在探究C12对体内外炎症进程的调控作用。在小鼠原代腹腔巨噬细胞模型中，C12可强效抑制促炎基因的表达及下游炎症介质的分泌，涉及的靶点包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、诱导型一氧化氮合酶（iNOS）、环氧合酶-2（COX-2）及前列腺素E合酶。C12的抗炎活性部分依赖于对细胞外调节蛋白激酶/ c-Jun氨基末端激酶（ERK/JNK，而非p38）的磷酸化抑制，以及对核因子κB（NF-κB）活化的阻断作用。体内实验结果显示，C12可抑制内毒素血症小鼠血浆与肝脏组织中的促炎细胞因子生成，减轻肺部病理损伤，并显著降低内毒素血症小鼠的死亡率。此外，预先给予C12可显著缓解乙酸诱导及福尔马林诱导模型中的炎性疼痛，同时减轻角叉菜胶诱发的小鼠足肿胀，并抑制乙酸诱导的血管通透性升高。综上，C12具备多重抗炎活性。结合其低毒性与水溶性特性，该化合物有望成为炎性疾病的潜在治疗候选药物。