Bacterial meningitis (BM) is the main cause of the central nervous system (CNS) infection and continues to be an important cause of mortality and morbidity. Glutathione (GSH), an endogenous tripeptide antioxidant, has been proved to exert crucial role in reducing superoxide radicals, hydroxyl radicals and peroxynitrites. The purpose of this study is to expand the application scope of GSH via exploring its therapeutic effect on BM caused by Salmonella typhimurium SL1344 and then provide a novel approach for the treatment of BM. The results suggested that intragastric administration of GSH could significantly increase median survival and improve experimental autoimmune encephalomyelitis score of BM model mice. However, exogenous GSH did not affect the adhesion, invasion and cytotoxicity of SL1344 to C6, BV2 and primary microglia. Due to the contradiction between the therapeutic and bactericidal effects of GSH, the effect of GSH on blood-brain barrier (BBB) was investigated to explore its action target for the treatment of meningitis. GSH was found to repair the damage of BBB and then prevent the leakage of SL1344 from the brain to the blood circulation. The repaired BBB could also effectively reduce the entry of macrophages and neutrophils into the brain, and significantly reverse the microglia activation induced by SL1344. More importantly, exogenous GSH was proved to reduce mouse brain cell apoptosis by inhibiting the activation of caspase-8 followed by caspase-3, and reversing the up-regulation of ICAD and PARP-1 caused by SL1344.

Graphical Abstract

中文翻译：

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口服 GSH 通过保护 BBB 完整性和抑制沙门氏菌诱导的细胞凋亡对实验性沙门氏菌脑膜炎发挥治疗作用

细菌性脑膜炎（BM）是中枢神经系统（CNS）感染的主要原因，并且仍然是死亡和发病的重要原因。谷胱甘肽（GSH）是一种内源性三肽抗氧化剂，已被证明在减少超氧自由基、羟基自由基和过氧亚硝酸盐方面发挥着至关重要的作用。本研究旨在探讨GSH对鼠伤寒沙门氏菌SL1344引起的BM的治疗作用，扩大GSH的应用范围，为BM的治疗提供新的途径。结果表明，灌胃GSH可显着提高BM模型小鼠的中位生存率并改善实验性自身免疫性脑脊髓炎评分。然而，外源GSH并不影响SL1344对C6、BV2和原代小胶质细胞的粘附、侵袭和细胞毒性。由于GSH的治疗作用和杀菌作用之间存在矛盾，因此研究GSH对血脑屏障(BBB)的影响，以探讨其治疗脑膜炎的作用靶点。GSH被发现可以修复BBB的损伤，然后防止SL1344从大脑渗漏到血液循环中。修复后的血脑屏障还可以有效减少巨噬细胞和中性粒细胞进入大脑，并显着逆转SL1344诱导的小胶质细胞活化。更重要的是，外源性GSH被证明可以通过抑制caspase-8和caspase-3的激活，并逆转SL1344引起的ICAD和PARP-1的上调来减少小鼠脑细胞凋亡。

图形概要