Abstract
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.
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Funding
This work was supported by the National Natural Science Foundation of China (Grant No.: 82274194); the Jiangsu Natural Science Funds (Grant No.: BK20211224); the Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University (Grant No.: SKLNMZZ202001) and the Natural Science Foundation of Hebei Province (Grant No.: H2020208022, H2020208025, H2021302001, C2021418001, H2021208006).
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This study was conceived and designed by LY, WGJ and CYG. GHM and JW were responsible for data curation, analysis and original draft writing. LSJ and XL provided the comprehensive technical support. MSY, LKAQ and ZZH contributed to the inspection of data and final manuscript. All authors read and approved the final manuscript.
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Huimin Guo, Wei Jin, and Keanqi Liu these authors contributed equally to this work.
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Guo, H., Jin, W., Liu, K. et al. Oral GSH Exerts a Therapeutic Effect on Experimental Salmonella Meningitis by Protecting BBB Integrity and Inhibiting Salmonella-induced Apoptosis. J Neuroimmune Pharmacol 18, 112–126 (2023). https://doi.org/10.1007/s11481-022-10055-6
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DOI: https://doi.org/10.1007/s11481-022-10055-6