Department of Neurology, University Hospital, LMU Munich, 81377, Munich, Germany.
Department of Neurology, Klinikum Grosshadern of the Ludwig Maximilians University, Marchioninistraße 15, 81377, Munich, Germany.
J Neuroinflammation. 2017 Nov 2;14(1):214. doi: 10.1186/s12974-017-0989-0.
Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis.
We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release.
Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former.
DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.
肺炎球菌性脑膜炎仍然是一种潜在致命且使人虚弱的疾病，主要是由于持续炎症导致的脑损伤。危险相关分子模式（DAMPs）的释放，如髓系细胞相关蛋白 14（MRP14）和高迁移率族蛋白 1 （HMGB1），在炎症持续中起着重要作用。在这项研究中，我们评估了 MRP14 抑制剂帕奎莫德和抗 HMGB1 抗体是否可以作为肺炎球菌性脑膜炎的辅助治疗来改善临床结果。
我们在肺炎球菌性脑膜炎小鼠模型中测试了帕奎莫德和抗 HMGB1 抗体的辅助给药，评估了临床（临床评分、旷场试验、体温）和病理生理参数（颅内压、CSF 中的白细胞计数、出血面积）以及血液和大脑中的细菌滴度 24 小时后给药和感染后 48 小时。此外，我们还探讨了这两种药物与地塞米松（肺炎球菌性脑膜炎的标准辅助治疗）和达托霉素（一种防止病原体相关分子模式（PAMP）释放的非杀菌抗生素）之间的相互作用。
辅助抑制 MRP14 或 HMGB1 可降低肺炎球菌性脑膜炎小鼠的死亡率。当同时给予两种抗 DAMPs 药物时，这种作用消失，可能是由于过度免疫抑制。联合使用抗 PAMP（达托霉素）和抗 DAMPs 治疗并没有产生协同作用；相反，单独使用抗 DAMPs 治疗就足够且更有效。抗 HMGB1 与地塞米松联合使用并没有降低前者的效果。
DAMPs 抑制作为肺炎球菌性脑膜炎的辅助治疗方法具有良好的潜力，因为它可以改善临床结果，并且可以与标准辅助药物地塞米松一起使用，而不会在实验性肺炎球菌性脑膜炎中损失药物效果。
