Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, PR China.
Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, PR China.
Biochem Biophys Res Commun. 2019 Sep 17;517(2):221-226. doi: 10.1016/j.bbrc.2019.07.045. Epub 2019 Jul 20.
The brain is one of the earliest organs to be influenced during sepsis. Sepsis-associated encephalopathy (SAE) is frequent, but seldomly recognized and has no testified pharmacological therapy. In this study, we demonstrated that pentamidine, an antiprotozoal drug, is a good candidate since it blocks S100B/RAGE/NF-κB signaling pathway. Pentamidine ameliorated cecal ligation and puncture (CLP)-induced brain damage assessed by crystal violet staining and hematoxylin and eosin (H&E) staining. Moreover, pentamidine reduced neuroinflammation in mouse hippocampi. Immunofluorescence and Western blot analysis also showed that pentamidine inhibited CLP-induced gliosis and S100B/RAGE/NF-κB pathway activation. Interestingly, it could also attenuate oxidative stress indicated by decreased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and attenuation of malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) consumption. Thus the S100B/RAGE/NF-κB pathway may be crucial in the pathogenesis of SAE and may be a promising pharmacological target to prevent SAE.
大脑是脓毒症早期受影响的器官之一。与脓毒症相关的脑病（SAE）很常见，但很少被认识到，也没有经过验证的药物治疗。在这项研究中，我们证明了戊烷脒是一种抗原生动物药物，是一种很好的候选药物，因为它可以阻断 S100B/RAGE/NF-κB 信号通路。戊烷脒通过结晶紫染色和苏木精和伊红（H&E）染色改善盲肠结扎和穿刺（CLP）诱导的脑损伤。此外，戊烷脒降低了小鼠海马中的神经炎症。免疫荧光和 Western blot 分析还表明，戊烷脒抑制了 CLP 诱导的神经胶质增生和 S100B/RAGE/NF-κB 通路激活。有趣的是，它还可以减轻氧化应激，表现为诱导型一氧化氮合酶（iNOS）和环加氧酶-2（COX-2）蛋白水平降低，丙二醛（MDA）积累减少，超氧化物歧化酶（SOD）消耗减少。因此，S100B/RAGE/NF-κB 通路可能在 SAE 的发病机制中起关键作用，可能是预防 SAE 的有前途的药物靶点。
